Anthranilic acid derivative

ABSTRACT

The present invention relates to an anthranilic acid derivative expressed by the following formula (1) or the following formula (2), or its pharmacologically permissible salt or solvate.

This is a divisional of Application No. 09/744,388 (Confirmation No. 5705) filed Apr. 4, 2001, which is a 371 of PCT Application No. PCT/JP99/03969, filed Jul. 23, 1999, the disclosure of which is incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to a new anthranilic acid derivative expressed by the formula (1) or the formula (2), its pharmacologically permissible salts or solvated products (which may be collectively called as “the anthranilic acid derivative of the present invention” hereinafter), a pharmaceutical composition composed thereof and a preventive and/or therapeutic agent composed thereof. More particularly, it relates to a new anthranilic acid derivative having benzene skeleton or pyridine skeleton on the principal anthranilic acid skeleton and further having a benzene skeleton or a naphthalene skeleton substituted by a side chain containing hetero-atom, i.e. a derivative having three aromatic groups at the same time, its pharmacologically permissible salt or solvated product, a pharmaceutical composition composed thereof and a preventive and/or therapeutic agent composed thereof.

Further, the anthranilic acid derivative of the present invention is a compound clinically applicable as a carcinostatic agent owing to its strong cytotoxic action and also clinically applicable as a preventive and/or therapeutic agent for allergic diseases owing to its activity to suppress the formation of IgE antibody.

BACKGROUND ARTS

Examples of the compound having naphthalene skeleton and anthranilic acid skeleton at the same time are those disclosed in the specification of JP-A 1-287066 (hereinunder, JP-A means “Japanese Unexamined Patent Application”). The specification describes compounds such as N-(2-naphthoyl)anthranylbenzoic acid and shows that these compounds have antiallergic activity or 5-lipoxygenase inhibiting activity. However, these compounds consist of a bicyclic aromatic ring derivative substituted by hydroxyl group or alkoxy group and directly bonded to an anthranilic acid skeleton through an amide bond, and there is no description or suggestion in the specification whether these compounds have cytotoxic action or IgE antibody production suppressing action or not.

Compounds having naphthalene skeleton and anthranilic acid skeleton and exhibiting antiallergic activity and IgE antibody production suppressing activity are described in the specifications of JP-A 1-106818, International Application WO90/12001 and JP-A 7-285858. However, these compounds are different from the compound of the present invention because there is no compound having a principal skeleton containing three aromatic rings at the same time in these compounds.

International Application WO95/32943 and a document “Journal of Medicinal Chemistry (J. Med. Chem.) vol. 40, No. 4, sections 395-407 (1997)” describe compounds having naphthalene skeleton and anthranilic acid skeleton and exhibiting antiallergic activity and IgE antibody production suppressing activity. Further, International Application WO97/19910 describes compounds having benzene skeleton and anthranilic acid skeleton and exhibiting antiallergic activity and IgE antibody production suppressing activity. However, these compounds are also different from the compound of the present invention because the substituent corresponding to the side chain of benzene skeleton or naphthalene skeleton is limited to alkoxy groups, alkenyloxy groups or aralkyloxy groups. Furthermore, the specification merely describes the presence of antiallergic activity and IgE antibody production suppressing activity in these compounds having the above specific substituents.

Compounds having pyridine ring skeleton and anthranilic acid skeleton and exhibiting antibacterial activity are described in the specification of International Application WO95/25723. The specification further describes that the substituent of the pyridine ring includes phenyloxy group and phenylthio group which may have substituents. However, there is no detailed explanation on the kind of the substituents. In the compounds of the present invention, for example, the pyridine ring is always substituted by phenyloxy group, phenylthio group, phenylsulfonyl group, phenylsulfinyl group, phenylcarbonyl group, phenylmethyl group, naphthyloxy group, naphthylthio group, naphthylsulfonyl group, naphthylsuifinyl group, naphthylcarbonyl group or naphthylmethyl group and furthermore the phenyl group or the naphthyl group constitutes the mother nucleus and always substituted by alkoxy group, aryloxy group, etc., which may contain hetero-atoms and, accordingly, the compound of the present invention is different from the compounds described in the above specification. Further, there is no comment on the IgE antibody production suppressing activity in the specification.

Meanwhile, the creation of a new compound having strong cytotoxic action is extremely important in the development of an excellent carcinostatic agent. Since the carcinostatic activity and carcinostatic spectrum of a compound are highly dependent upon its chemical structure in general, it is highly possible to enable the development of a carcinostatic agent having excellent characteristics compared with conventional carcinostatic agents practically in use at present from a cytotoxic compound having a new structure different from the structure of known compounds.

Examples of known low-molecular compound having benzene skeleton or aryl skeleton and exhibiting cytotoxic activity are substituted phenylsulfonyl derivative (JP-A 5-9170), 2-arylquinolinol derivative (JP-A 7-33743) and benzoylacetylene derivative (JP-A 7-97350).

However, the fact that a compound having benzene skeleton or aryl skeleton together with anthranilic acid skeleton has cytotoxic activity or carcinostatic activity is utterly unknown.

The object of the present invention is to provide a new compound usable as a clinically applicable therapeutic agent for cancer and preventive and/or therapeutic agent for allergic diseases.

DISCLOSURE OF THE INVENTION

As a result of vigorous investigation performed by the inventors of the present invention to achieve the above purpose, the inventors have found the following items 1 to 16 and completed the present invention.

In the description of atomic group expressing substituent, etc., the mark “-” showing the direction of bond is described in a group supposed to have ambiguous bonding form, however, the mark may be omitted for a group having clear bonding form.

-   1. The anthranilic acid derivative expressed by the following     formula (1) or the following formula (2) or its pharmacologically     permissible salt or solvate.           -   <<in the formulas, Y¹ is the group of the following formula         (3)-1 or (3)-2.               -   {in the formulas, Z is a straight-chain, branched or cyclic         saturated, unsaturated or aromatic C1 to C12 hydrocarbon group         substituted by one or more —NR¹⁰R¹¹, —COOR¹², —(C═O)NR¹³R¹⁴,         —(C═O)R¹⁵ or OR¹⁶ [the C1 to C12 hydrocarbon group is optionally         substituted by a substituent L (L is a C1 to C6 alkyl group, a         halogen atom, —NO₂ or —CN)],     -   a 3 to 8-membered saturated ring containing one or plural         —NR¹⁷—, —O— or —S— in the ring and optionally containing one or         more —C(═O)— groups in the ring, a C1 to C4 straight or         branched-chain saturated or unsaturated hydrocarbon group having         one or two double bonds or triple bonds and optionally         substituted by the above 3 to 8-membered ring, or a C5 to C10         straight or branched-chain saturated or unsaturated hydrocarbon         group substituted by a monocyclic or bicyclic aromatic ring         containing one or more hetero-atoms selected from oxygen,         nitrogen and sulfur atom in the ring (the aromatic ring is         optionally substituted by the substituent L).     -   the groups R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are each         independently hydrogen atom, a straight or branched-chain C1 to         C6 alkyl group which is optionally substituted, a C7 to C11         aralkyl group which is optionally substituted, a C6 to C10 aryl         group which is optionally substituted (the substituent is a         halogen atom, —OH, a C1 to C4 alkoxy group, —CN, —NO₂ or         —COOR¹⁸), or a group selected from the following formulas (4)-1,         (4)-2 and (4)-3. The groups R¹⁰ and R¹¹, or R¹³ and R¹⁴ may         together form a 3 to 12-membered ring optionally containing one         or more —O—, —S—, —NR¹⁸— or —(C═O)— groups.               -   {in the formulas, Q is a C1 to C10 alkyl group which is         optionally substituted, a C2 to C6 alkenyl group which is         optionally substituted, a C1 to C6 alkoxy group which is         optionally substituted, a C7 to C11 aralkyl group which is         optionally substituted, a C7 to C11 aralkyloxy group which is         optionally substituted (the substituent is a halogen atom, —OH,         —CN, —NO₂, —COOR¹⁹ or phenoxy group), dimethylamino group,         morpholino group or a monocyclic or bicyclic aromatic         hydrocarbon group which may have one or more hetero-atoms         selected from oxygen, nitrogen and sulfur atoms. [when a         monocyclic or bicyclic aromatic hydrocarbon group which may have         one or more hetero-atoms is selected in the above case, the ring         is optionally substituted at arbitrary positions independently         by one or plural substituents selected from halogen atom, —OH,         —NO₂, —CN, —COOR¹⁹, —NR¹⁹R²⁰, straight or branched-chain C1 to         C6 alkyl group, straight or branched-chain C1 to C6 alkoxy group         (in this case, the substituents at adjacent positions may form         an acetal bond), straight or branched-chain C1 to C6 alkylthio         group, straight or branched-chain C1 to C6 alkylsulfonyl group,         straight or branched-chain C1 to C6 acyl group, straight or         branched-chain C1 to C6 acylamino group, trihalomethyl group,         trihalomethoxy group, phenyl group, or phenoxy group which is         optionally substituted by one or more halogen atoms],     -   the groups R¹⁹ and R²⁰ are each independently hydrogen atom or a         C1 to C4 alkyl group],     -   the group R¹⁸ is hydrogen atom or a C1 to C4 alkyl group,     -   the group X³ is —(C═O)—, —O—, —S—, —(S═O)—, SO₂, —NR²¹—,         *—NR²¹(C═O) or *—(C═O)NR²¹ (the sign (*—) representing a bond         means the bonding to the benzene ring or the naphthalene ring in         the formula (3)-1 or the formula (3)-2),     -   the group R²¹ is hydrogen atom or a C1 to C4 hydrocarbon group         which is optionally substituted by a halogen,     -   the groups R⁵ and R⁶ are each independently hydrogen atom, a         halogen atom, —NO₂, —CO₂H, —CN, —OR²², —NH(C═O)R²², —(C═O)NHR²²         or a C1 to C4 straight or branched-chain saturated or         unsaturated hydrocarbon group which is optionally substituted by         halogen atom,     -   the group R²² is a C1 to C3 hydrocarbon group which is         optionally substituted by hydrogen atom or halogen atom},     -   the group Y² is the formula (3)-1, the formula (3)-2, the         following formula (5)-1 or the following formula (5)-2,               -   <in the formulas, the group R⁷ is hydrogen atom or a substituted         or unsubstituted straight-chain, branched or alicyclic saturated         or unsaturated C1 to C12 hydrocarbon group having one or two         double bonds or triple bonds [in this case, the substituent is a         halogen atom, —NO₂, —CN, a substituted or unsubstituted phenyl         group (in this case, the substituent is a halogen atom, —NO₂,         —CN, —CF₃ or a C1 to C4 hydrocarbon group), or a substituted or         unsubstituted 5 to 8-membered cycloalkyl group (in this case,         the substituent is a halogen atom or a C1 to C4 hydrocarbon         group)],     -   the group X⁴ is —(C═O)—, —O—, —S—, —(S═O)—, —(O═S═O)—, —NR²³—,         *—NR²³CO or *—CONR²³ (the group R²³ is hydrogen atom or a C1 to         C4 hydrocarbon group which is optionally substituted by halogen         atom. In this case, the sign (*—) means the bonding to the         benzene ring or the naphthalene ring of the formula (5)-1 or the         formula (5)-2. The group R⁷ is not hydrogen atom when the group         X⁴ is —(C═O)—, —(S═O)—, —(O═S═O)— or *—NR²³(C═O)—,     -   the groups R⁸ and R⁹ are each independently hydrogen atom, a         halogen atom, —NO₂, —CO₂H, —CN, —OR²⁴, —NH(C═O)R²⁴, —(C═O)NHR²⁴         or a straight or branched-chain saturated or unsaturated C1 to         C4 hydrocarbon group which is optionally substituted by halogen         atom (the group R²⁴ is hydrogen atom or a C1 to C3 hydrocarbon         group which is optionally substituted by halogen atom)>,     -   the group X¹ is —(C═O)—, —O—, —S—, —(S═O)—, —(O═S═O)— or —CH₂—,     -   the group X² is O or S,     -   the groups R¹ and R² are each independently hydrogen atom, a         halogen atom, —NO₂, —CO₂H, —CN, —OR²⁵, —NH(C═O)R²⁵, —(C═O)NHR²⁵         or a C1 to C4 straight or branched-chain saturated or         unsaturated hydrocarbon group which is optionally substituted by         halogen atom,     -   the group R²⁵ is hydrogen atom or a C1 to C3 hydrocarbon group         which is optionally substituted by halogen atom,     -   the groups R³ and R⁴ are each independently hydrogen atom or a         C1 to C4 hydrocarbon group,     -   the group A is N, N→O or N⁺—CH₃, and     -   n is an integer of 0 to 3.>>. -   2. The above anthranilic acid derivative wherein Y² is the group of     the formula (3)-1 or the formula (3)-2 or its pharmacologically     permissible salt or solvate. -   3. An anthranilic acid derivative expressed solely by the formula     (1), or its pharmacologically permissible salt or solvate. -   4. An anthranilic acid derivative expressed solely by the     formula (2) wherein the group Y² is expressed by the formula (3)-1     or the formula (3)-2, or its pharmacologically permissible salt or     solvate. -   5. An anthranilic acid derivative expressed solely by the     formula (2) wherein the group Y² is expressed by the formula (5)-1     or the formula (5)₂, or its pharmacologically permissible salt or     solvate. -   6. An anthranilic acid derivative of the formula (1) wherein the     group Y¹ is expressed by the following formula (9)-1, (9)-2 or     (9)-3, or its pharmacologically permissible salt or solvate.           -   <in the formula, the definitions of Z, X³, R⁵ and R⁶ are same as         those of the formula (3)-1 or the formula (3)-2>. -   7. An anthranilic acid derivative of the formula (2) wherein the     group Y² is expressed by the formula (5)-1, the formula (5)-2, the     formula (9)-1, the formula (9)-2 or the formula (9)-3, or its     pharmacologically permissible salt or solvate. -   8. The anthranilic acid derivative of the formula (1) or the     formula (2) wherein the group Z is a straight-chain, branched or     cyclic saturated, unsaturated or aromatic C1 to C12 hydrocarbon     group substituted by one or more —NR¹⁰R¹¹, —COOR¹², —(C═O)NR¹³R¹⁴,     —(C═O)R¹⁵ or —OR¹⁶ [the C1 to C12 hydrocarbon group is optionally     further substituted by substituent L (L is a C1 to C6 alkyl group,     halogen atom, —NO₂ or —CN)], or its pharmacologically permissible     salt or solvate. -   9. An anthranilic acid derivative of the formula (1) or the     formula (2) wherein the group Z is a saturated 3 to 8-membered ring     containing one or plural —NR¹⁷—, —O— or —S— groups and optionally     containing one or more —C(═O)—groups in the ring, or a C1 to C4     straight or branched-chain saturated or unsaturated hydrocarbon     group having one or two double bonds or triple bonds and optionally     substituted by the above 3 to 8-membered ring, or its     pharmacologically permissible salt or solvate. -   10. The anthranilic acid derivative of the formula (1) or the     formula (2) wherein the group Z is a C5 to C10 straight or     branched-chain saturated or unsaturated hydrocarbon group     substituted by a monocyclic or bicyclic aromatic ring containing one     or more hetero-atoms selected from oxygen, nitrogen and sulfur atom     in the ring (the aromatic ring is optionally substituted by a     substituent L), or its pharmacologically permissible salt or     solvate. -   11. A pharmaceutical composition composed of the above anthranilic     acid derivative or its pharmacologically permissible salt or     solvate, and a pharmacologically permissible carrier. -   12. The above pharmaceutical composition having cytotoxic activity. -   13. A therapeutic agent for cancer composed of the above     pharmaceutical composition. -   14. The above pharmaceutical composition having IgE antibody     production suppressing action. -   15. A preventive or therapeutic agent for allergic diseases composed     of the above pharmaceutical composition. -   16. The above preventive or therapeutic agent wherein said allergic     diseases are bronchial asthma, allergic rhinitis, allergic     conjunctivitis, atopic dermatitis, anaphylactic shock, mite allergy,     pollinosis, food allergy, urticaria, ulcerative colitis,     eosinophilic gastroenteritis or drug-induced rash.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is described in more detail as follows.

In the formula (1) expressing the anthranilic acid derivative of the present invention, Y¹ is a group selected from the formula (3)-1 and the formula (3)-2.

 

In the formulas, ZX³, R⁵ and R⁶ are substituted one for each to the benzene ring or the naphthalene ring, however, the group ZX³— is preferably positioned at a site expressed in the following formulas (9)-1 to (9)-3.

 

R⁵ and R⁶ are each independently hydrogen atom, a halogen atom, —NO₂, —CO₂H, —CN, —OR²², —NH(C═O)R²² or —(C═O)NHR²² or a C1-C4 straight or branched-chain saturated or unsaturated hydrocarbon group which may be substituted by halogen atom, and preferably hydrogen atom, a halogen atom, —NO₂, —CN, —OH, —OCH₃, —NH(C═O)CH₃, —(C═O)NHCH₃ or a C1-C4 straight or branched-chain saturated or unsaturated hydrocarbon group which may be substituted by halogen atom. More preferably, it is hydrogen atom, a halogen atom, —CH₃, —OH or —OCH₃ and, especially, hydrogen atom.

In the formula (3)-1 or the formula (3)-2, Z is a C1-C12 (the carbon number is restricted to those allowable from its structure) straight, branched or cyclic saturated or unsaturated hydrocarbon group or aromatic hydrocarbon group substituted by one or more substituents selected from —NR¹⁰R¹¹, —COOR¹², —(C═O)NR¹³R¹⁴, —(C═O)R¹⁵ and —OR¹⁶ and optionally substituted by a substituent L, or a saturated 3 to 8-membered ring having one or plural NR¹⁷, O or S in the ring and optionally containing one or more —C(═O)— groups in the ring or a C5-C10 straight or branched-chain saturated or unsaturated hydrocarbon group substituted by a C1-C4 straight or branched-chain or unsaturated hydrocarbon group having one or two double bonds or triple bonds and optionally substituted by the above 3 to 8-membered ring or by a monocyclic or bicyclic aromatic ring (which may be substituted by the substituent L) containing one or more hetero-atoms selected from oxygen, nitrogen and sulfur. The carbon number of the C1-C12 hydrocarbon group of Z is the number of carbon atoms of the main chain and the carbon numbers of the substituents are not included in the carbon number.

When the group Z is a C1-C12 straight, branched or cyclic saturated or unsaturated hydrocarbon or an aromatic hydrocarbon, it is for example methyl group, ethyl group, propyl group, butyl group, isobutyl group, hexyl group, 2-ethylpropyl group, 1,1-dimethylethyl group, allyl group, methallyl group, cyclohexyl group, cyclooctyl group, cyclopentylmethyl group, cyclohexenylmethyl group, 1-decalyl group, phenyl group, benzyl group and phenylpropyl group, and especially preferably methyl group, ethyl group, cyclohexyl group, cydopentylmethyl group, benzyl group or phenylpropyl group. These hydrocarbon groups are substituted by one or more —NR¹⁰R¹¹, —COOR¹², —(C═O)NR¹³R¹⁴, —(C═O)R¹⁵ or —OR¹⁶ groups.

In the definitions of the formula (3)-1 and the formula (3)-2, the group Z is a saturated 3 to 8-membered ring containing one or plural —NR¹⁷—, —O— or —S— groups in the ring and optionally containing one or more —C(═O)— groups, or a C1-C4 straight or branched-chain saturated hydrocarbon group or unsaturated hydrocarbon group containing one or two double bonds or triple bonds wherein these hydrocarbon groups may be substituted by the above 3 to 8-membered ring.

When Z is a C1-C4 straight or branched-chain saturated hydrocarbon group or unsaturated hydrocarbon group containing one or two double bonds or triple bonds wherein these hydrocarbon groups may be substituted by a saturated 3 to 8-membered ring containing one or plural —NR¹⁷—, —O— or —S— groups in the ring and optionally containing one or more —C(═O)— groups, the number of carbon atoms of the C1-C4 hydrocarbon does not include the carbon number of the ring. The substitution position of the main chain on the ring is an arbitrary carbon atom constituting the ring. In the above sentence, the main chain means a C1-C4 straight or branched-chain saturated hydrocarbon group or unsaturated hydrocarbon group containing one or two double bonds or triple bonds.

When the group Z is a saturated 3 to 8-membered ring containing one or plural —NR¹⁷—, —O— or —S— groups in the ring and optionally containing one or more —C(═O)— groups, the substitution position of the group X³ defined in the formula (3)-1 and the formula (3)-2 is an arbitrary carbon atom constituting the ring.

The saturated 3 to 8-membered ring containing one or plural —NR¹⁷—, —O— or —S— groups in the ring and optionally containing one or more —C(═O)— groups is, for example, pyrrolidine ring, piperidine ring, pyrrolidone ring, piperazine ring, morpholine ring, thiomorpholine ring, tetrahydropyran ring and tetrahydrothiophene ring and especially preferably pyrrolidine ring, piperidine ring and piperazine ring.

In the C1-C4 straight or branched-chain saturated hydrocarbon group or unsaturated hydrocarbon group having one or two double bonds or triple bonds and substituted by a 3 to 8-membered ring, the straight-chain group is e.g. methyl group, ethyl group, n-propyl group, n-butyl group, 2-propenyl group, 3-butenyl group and 2-propynyl group, preferably methyl group, ethyl group, n-propyl group or n-butyl group, especially preferably methyl group or ethyl group.

The branched-chain group is e.g. isopropyl group, t-butyl group and 2-methylpropyl group and, among the above examples, isopropyl group and t-butyl group are preferable. In the definition in the formula (3)-1 and the formula (3)-2, the group Z is a C5-C10 straight or branched-chain saturated or unsaturated hydrocarbon group substituted by monocyclic or bicyclic aromatic ring (the aromatic ring may be substituted by a substituent L) containing one or more hetero-atoms selected from oxygen, nitrogen and sulfur atom in the ring.

The term “C5-C10” means the total number of carbon atoms including the carbon atoms of substituents.

The monocyclic or bicyclic aromatic ring containing one or more hetero-atoms selected from oxygen, nitrogen and sulfur atom in the ring is, for example, pyridine ring, furan ring, thiophene ring, quinoline ring, pyrazole ring, imidazole ring, thiazole ring, triazole ring, benzofuran ring, thianaphthalene ring, indole ring and benzimidazole ring. Among the above examples, pyridine ring, furan ring, thiophene ring and quinoline ring are preferable and pyridine ring is especially preferable.

Examples of the C5-C10 straight or branched-chain saturated or unsaturated hydrocarbon group substituted by these aromatic rings are 4-pyridylmethyl group, 3-furanylmethyl group, 3-thiophenylethyl group, 2-quioline-4-ylmethyl group and 3-pyridylethyl group and especially preferably 4-pyridylmethyl group.

The monocyclic or bicyclic aromatic ring containing one or more hetero-atoms selected from oxygen, nitrogen and sulfur atom in the ring may be substituted by a substituent L, and such substituent L is selected from C1-C6 alkyl group, halogen atom, —NO₂ and —CN, for example, methyl group, ethyl group, isobutyl group, 1-ethylpropyl group, chloro group, bromo group, nitro group and nitrile group and, among the above examples, methyl group, ethyl group and chloro group are preferable.

The groups R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are each independently hydrogen atom, a C1-C6 straight or branched-chain alkyl group which may have substituent, a C7-C11 aralkyl group which may have substituent, a C6-C10 aryl group which may have substituent (these substituents are halogen atom, OH, C1-C4 alkoxy group, —CN, —NO₂ or —COOR¹⁸), or a group selected from the formula (4)-1, the formula (4)-2 and the formula (4)-3 or R¹⁰ and R¹¹, or R¹³ and R¹⁴ together form a 3 to 12-membered ring which may contain one or more —O—, —S—, —NR¹⁸— or —(C═O)— groups in the ring. Preferable examples of the groups R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are hydrogen atom, a C1-C6 straight or branched-chain alkyl group which may have substituents, a C7-C11 aralkyl group which may have substituents, a C6-C10 aryl group which may have substituents (these substituents are C1-C4 alkoxy group or COOR¹⁸) or a group selected from the formula (4)-1, the formula (4)-2 and the formula (4)-3.

 

When these groups are hydrogen atom, a C1-C6 straight or branched-chain alkyl group which may have substituents, a C7-C11 aralkyl group which may have substituents or a C6-C10 aryl group which may have substituents, examples of the groups are hydrogen atom, methyl group, ethyl group, isopropyl group, n-butyl group, pentyl group, hexyl group, benzyl group, phenyl group and naphthyl group, preferably methyl group, ethyl group, benzyl group and phenyl group. These group may be substituted by halogen atom, —OH, a C1-C4 alkyl group, —CN, —NO₂ or —COOR¹⁸, and the substituent is preferably —Cl, —OH, ethoxy group, —CN or —COOH.

When the groups R¹⁰ and R¹¹ or R¹³ and R¹⁴ together form a 3 to 12-membered ring, the ring may contain O, S or NR¹⁸. Concretely, the ring is e.g. pyrrolidine ring, piperidine ring, pyrrolidone ring, piperazine ring, morpholine ring, thiomorpholine ring, etc., and above all, pyrrolidine ring, piperidine ring, piperazine ring and morpholine ring are preferable. When the ring is e.g. piperazine ring, the nitrogen atom of the ring may be substituted by a C1-C4 lower alkyl group, i.e. R¹⁸, and in this case, the substituent is especially preferably methyl group or isopropyl group.

In the formula (3)-1 or the formula (3)-2, the group X³ is —(C═O)—, —O—, —S—, —(S═O)—, —(O═S═O)—, —NR²¹, *—NR²¹(C═O)— or *—(C═O)NR² (the sign (*—) representing a bond means the bonding to the benzene ring or the naphthalene ring). The group is e.g. —(C═O)—, —O—, —S—, —N(CH₃)(C═O)— or —(C═O)NCH₃ and especially preferably —O— or —S—.

In the formula (4)-1, the formula (4)-2 and the formula (4)-3, the group Q is a C2-C10 alkyl group which may have substituents, a non-substituted C1-C6 alkenyl group which may have substituents, a C1-C6 alkoxy group which may have substituents, a C7-C11 aralkyl group which may have substituents, a C7-C11 aralkyloxy group which may have substituents, dimethylamino group, morpholino group or a monocyclic or bicyclic aromatic hydrocarbon group which may contain one or plural hetero-atoms selected from oxygen, nitrogen and sulfur atom in the ring.

When the group Q is a C1-C10 alkyl group which may have substituents, a C1-C6 alkenyl group which may have substituents, a C1-C6 alkoxy group which may have substituents, a C7-C11 aralkyl group which may have substituents, a C7-C11 aralkyloxy group which may have substituents, the concrete examples of the group are methyl group, ethyl group, propyl group, heptyl group, methoxy group, allyl group, benzyl group, phenylpropyl group and benzyloxy group. These groups may be substituted by halogen atom, —OH, —CN, —NO₂, —COOR¹⁹ or phenoxy group. Concretely, preferable substituent is chloro group, —OH, —COOH or phenoxy group.

When the group Q is a monocyclic or bicyclic aromatic hydrocarbon group which may contain one or plural hetero-atoms selected from oxygen, nitrogen and sulfur atoms in the ring, any one of the groups described in the following formula (10) can be selected as the aromatic hydrocarbon group.

 

These groups are bonded to the amide group, carboxyl group or sulfonyl group in the formula (4)-1, the formula (4)-2 or the formula (4)-3 as the group Q at an arbitrary possible position, and may be bonded with the following groups at the remaining positions. Namely, the groups may be substituted by one or plural groups independently selected from halogen atom, —OH, —NO₂, —CN, —COOR¹⁹, —NR¹⁹R²⁰, a straight or branched-chain C1-C6 alkyl group, a straight or branched-chain C1-C6 alkoxy group (in this case, an acetal bond may be formed at the sites adjacent to each other as the substituents), a straight or branched-chain C1-C6 alkylthio group, a straight or branched-chain C1-C6 alkylsulfonyl group, a straight or branched-chain C1-C6 acyl group, a straight or branched-chain C1-C6 acylamino group, trihalomethyl group, trihalomethoxy group, phenyl group, or phenoxy group which may be substituted by one or more halogen atoms. In the above description, R¹⁹ and R²⁰ are each hydrogen atom or a C1-C4 lower alkyl group.

Concrete examples of preferable substituents are —COOH, —F, —Cl, —Br, —NO₂, —OH, —NH₂, —NHCH₃, —N(CH₃)₂, —NH(C═O)CH₃, —(C═O)CH₃, —CF₃, —OCF₃, —CN, —OCH₃, —Ph, —CH₃, —(O═S═O)—, —CH₃, —SCH₃ and —OPh.

In the above formula (2), Y² is the group of formula (3)-1, the formula (3)-2, the formula (5)-1 or the formula (5)-2. Among the groups expressed by the formula (3)-1 or the formula (3)-2, the preferable groups are, as mentioned before, the groups of the formula (9)-1, (9)-2 or (9)-3.

 

In the formula (5)-1 or the formula (5)-2, the group R⁷ is hydrogen atom or optionally substituted straight, branched or alicyclic C1-C12 saturated hydrocarbon group or unsaturated hydrocarbon group containing one or two double bonds or triple bonds [in this case, the substituent is halogen atom, —NO₂, —CN, an optionally substituted phenyl group (the substituent is halogen atom, —NO₂, —CN, —CF₃ or a C1-C4 hydrocarbon group) or an optionally substituted 5 to 8-membered cycloalkyl group (the substituent is halogen atom or a C1-C4 hydrocarbon group)].

Each of the above groups has a total carbon number of 1 to 12 including the substituents. The cyclic saturated hydrocarbon group or unsaturated hydrocarbon group having one or two double bonds or triple bonds does not include aromatic rings such as benzene ring and hetero-aromatic ring, and the ring is directly bonded to the group X⁴ in the formula (5)-1 or the formula (5)-2. That is to say, the cyclic means alicyclic. In other words, these rings are free from oxygen, sulfur, nitrogen atom and carbonyl group in the ring, and the preferable examples of the ring are cyclopropane ring, cyclobutane ring, cyclopentane ring, cydohexane ring, cyclooctane ring, cycloheptane ring, cyclododecane ring, norbornene ring and cyclohexene ring. Cyclopentane ring, cyclohexane ring, cyclooctane ring and cyclododecane ring are more preferable among the above examples.

The straight-chain saturated hydrocarbon group or unsaturated hydrocarbon group having one or two double bonds or triple bonds is, for example, methyl group, ethyl group, n-propyl group, n-butyl group, n-hexyl group, n-octyl group, n-dodecyl group, 2-propenyl group, 3-butenyl group, 4-hexenyl group, 3-hexenyl group, 3-nonenyl group, 2,4-hexadienyl group and 2-propynyl group, preferably methyl group, ethyl group, n-propyl group, n-butyl group, n-hexyl group, 2-propenyl group, 3-butenyl group, 4-hexenyl group, 3-hexenyl group, 2,4-hexadienyl group or 2-propynyl group.

The branched saturated or unsaturated hydrocarbon group is, for example, isopropyl group, t-butyl group, ethylpropyl group, ethylpentyl group, 4-methylpentyl group, 2-ethylbutyl group, 2-methylpropyl group, 2-methylbutyl group, 2,4,4-trimethylpentyl group, 2-methylheptyl group, 3-methyl-1-(2-methylpropyl)butyl group, 2-methyl-1-(methylethyl)propyl group, 3-methyl-3-butenyl group, 3-methyl-2-butenyl group, 1-vinyl-2-propenyl group, 4-methyl-3-pentenyl group, 1-allyl-3-butenyl group, 1-ethyl-2-propenyl group, 1-propyl-2-propenyl group and 1-ethyl-2-propynyl group. Symmetric groups are preferable among the above groups. Especially preferable groups are ethylpropyl group and 2-ethylbutyl group.

The substituent of R⁷ is halogen atom, —NO₂, —CN, a substituted or non-substituted phenyl group (the substituent is selected from halogen atom, —NO₂, —CN, —CF₃ and C1-C₄ hydrocarbon group) and a substituted or non-substituted 5 to 8-membered cycloalkyl group (the substituent is selected from halogen atom and a C1-C4 hydrocarbon group).

In the substituent of R⁷ the substituted or non-substituted phenyl group (the substituent is selected from halogen atom, —NO₂, —CN, —CF₃ and a C1-C4 hydrocarbon group) is, for example, phenyl group, m-fluorophenyl group, p-chlorophenyl group, m-iodophenyl group, p-fluorophenyl group, 2,4-dichlorophenyl group, 3,5-difluorophenyl group, p-nitrophenyl group, m-nitrophenyl group, p-methylthiophenyl group, o-cyanophenyl group, p-cyanophenyl group, m-trifluoromethylphenyl group, p-methylphenyl group, p-isopropylphenyl group, p-t-butylphenyl group and 3,4-dimethylphenyl group.

The 5 to 8-membered cycloalkyl group as the substituent of the group R⁷ may be substituted by halogen atom or C1-C4 hydrocarbon group. Preferable examples of the C1-C4 hydrocarbon group are methyl group and ethyl group. Namely, examples of the optionally substituted 5 to 8-membered cycloalkyl group are cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, 2-chlorocyclohexyl group, 2-methylcydohexyl group, 2-ethylcyclohexyl group, 3-methylcyclohexyl group, 4-methylcydohexyl group, 4-(i-propyl)cyclohexyl group, 2,6-dimethylcyclohexyl group and 3,5-dimethylcyclohexyl group.

The group R⁷ is preferably hydrogen atom, a straight or branched-chain C1-C12 saturated hydrocarbon group or unsaturated hydrocarbon group having one or two double bonds or triple bonds and optionally substituted by halogen atom, or a group expressed by the following formulas.

 

-   -   [in the formula, n¹ is an integer of 1 to 3, n³ is an integer of         0 to 3, n² is an integer of 0 to 9 (when n³ is 0) or an integer         of 2 to 5 (when n³ is an integer of 1 to 3), R²⁶ and R²⁷ are         each independently hydrogen atom, halogen atom, NO₂, CN, CF₃ or         a C1-C4 hydrocarbon group, and R²⁸ is hydrogen atom or a C1-C4         hydrocarbon group]. (The groups R²⁶ and R²⁷ are more preferably         hydrogen atom, halogen atom or NO₂).

The group R⁷ is especially preferably hydrogen atom or a group selected from the groups expressed by the following formula (12).

 

The group X⁴ in the formula (5)-1 or the formula (5)-2 is —(C═O)—, —O—, —S—, —(S═O)—, —(O═S═O)—, —NR²³—, *—NR²³(C═O)— or *—(C═O)NR²³. (The sign (−) representing a bond is bonded to the benzene ring or the naphthalene ring having R⁸ and R⁹, R²³ is hydrogen atom or a C1-C4 hydrocarbon group which may be substituted by halogen atom. R¹ is not hydrogen atom when X⁴ is —(C═O)—, —S═O)—, (O═S═O)— or *—NR²³(C═O)—.). X⁴ is preferably —O—, —S—, —(S═O)— or —(O═S═O)—, more preferably —O— or —S— and especially preferably —O—.

R²³ is preferably hydrogen atom, methyl group or ethyl group, especially preferably hydrogen atom.

In the formula (5)-1 and the formula (5)-2, the groups R⁸ and R⁹ are each independently hydrogen atom, halogen atom, —NO₂, —CO₂H, —CN, —OR²⁴, —NH(C═O)R²⁴, —(C═O)NHR²⁴ or a straight or branched-chain saturated or unsaturated C1-C4 hydrocarbon group which may be substituted by halogen atom (the group R²⁴ is hydrogen atom or a C1-C3 hydrocarbon group which may be substituted by halogen atom.). It is preferably hydrogen atom, halogen atom, —NO₂, —CN, —OH, —OCH₃, —NH(C═O)CH₃, —(C═O)NHCH₃ or a straight or branched-chain saturated or unsaturated C1-C4 hydrocarbon group which may be substituted by halogen atom. It is more preferably hydrogen atom, halogen atom, —CH₃, —OCH₃, —OH, ethyl group, isopropyl group, t-butyl group, allyl group or trifluoromethyl group, further preferably hydrogen atom, halogen atom, —CH₃, —OCH₃, —OH or trifluoromethyl group and especially preferably hydrogen atom.

When the group R²⁴ is a C1-C3 hydrocarbon group which may be substituted by halogen, it is, for example, methyl group, ethyl group, isopropyl group and trifluoromethyl group and preferably methyl group or trifluoromethyl group.

In the formula (1) or the formula (2), X¹ is —(C═O)—, —O—, —S—, —(SO)—, —(O═S═O)— or —CH₂—, preferably —O—, —S—, —(S═O)— or —(O═S═O)—, especially preferably —O— or —S—.

In the formula (1) or the formula (2), X² is O or S, preferably O.

In the formula (1) or the formula (2), R¹ and R² are each independently hydrogen atom, halogen atom, —NO₂, —CO₂H, —CN, —OR²⁵, —NH(C═O)R²⁵, —(C═O)NHR²⁵ or a C1-C4 straight or branched-chain saturated or unsaturated hydrocarbon group which may be substituted by halogen atom. Concrete examples of the groups are hydrogen atom, chloro group, bromo group, —NO₂, —CO₂H, —CN, methoxy group, ethoxy group, chloromethoxy group, butoxy group, acetylamide group, propionylamide group, methylaminocarbonyl group, butylaminocarbonyl group, methyl group, bromoethyl group, allyl group and chloropropenyl group, and preferably hydrogen atom, halogen atom (especially chloro group), —OH, —NO₂, —CO₂H, —CN, methoxy group, chloromethoxy group, acetylamide group, methylaminocarbonyl group or methyl group.

In the formula (1) or the formula (2), R³ and R⁴ are each independently hydrogen atom or a C1-C4 hydrocarbon group. Concrete examples of the groups are hydrogen atom, methyl group, ethyl group, propyl group and butyl group and preferably hydrogen atom or methyl group.

In the formula (1) or the formula (2), n is an integer of 0 to 3, preferably 0 or 1.

In the formula (2), A is N, N→O or N⁺—CH₃, preferably N or N→O, more preferably N.

The anthranilic acid derivative of the present invention or its pharmacologically permissible salt can be converted into solvate at need. The solvent usable in the conversion process is water, methanol, ethanol, (n- or i-)propyl alcohol, (n- or t-)butanol, acetonitrile, acetone, methyl ethyl ketone, chloroform, ethyl acetate, diethyl ether, t-butyl methyl ether, benzene, toluene, DMSO, DMF, etc., preferably water, methanol, ethanol, (n- or i-)propyl alcohol or acetonitrile.

When the compound of the formula (1) or the formula (2) has CO₂H group in the molecule, the anthranilic acid derivative of the present invention can be converted as necessary into a non-toxic cation salt or its solvate. Examples of such salt are alkali metal ion such as Na⁺ and K⁺, alkaline earth metal ion such as Mg²⁺ and Ca²⁺, metal ion such as Al³⁺ and Zn²⁺, or organic base such as ammonia, triethylamine, ethylenediamine, propanediamine, pyrrolidine, piperidine, piperazine, pyridine, lysine, choline, ethanolamine, N,N-dimethylethanolamine, 4-hydroxypiperidine, glucosamine, and N-methylglucamine, preferably Na⁺, Ca²⁺, lysine, choline, N,N-dimethylethanolamine and N-methylglucamine. The solvents for forming the solvates of these salts are, for example, water, methanol, ethanol, (n- or i-)propyl alcohol, (n- or t-)butanol, acetonitrile, acetone, methyl ethyl ketone, chloroform, ethyl acetate, diethyl ether, t-butyl methyl ether, benzene, toluene, DMF and DMSO, especially preferably water, methanol, ethanol, (n- or i-)propyl alcohol and acetonitrile.

When the compound of the formula (1) or the formula (2) contains primary, secondary or tertiary amine group in the molecule, the anthranilic acid derivative of the present invention can be converted as necessary into an acid addition salt or its solvate. The acid for the production of the acid addition salt is a mineral acid such as hydrochloric acid, sulfuric acid and nitric acid or an organic acid such as acetic acid, benzoic acid, fumaric acid, maleic acid, methanesulfonic acid and toluenesulfonic acid. Preferable acids among the above examples are hydrochloric acid, sulfuric acid, acetic acid, fumaric acid, maleic acid, methanesulfonic acid and toluenesulfonic acid. The solvent for the production of the solvate of the salt is, for example, water, methanol, ethanol, (n- or i-)propyl alcohol, (n- or t-)butanol, acetonitrile, acetone, methyl ethyl ketone, chloroform, ethyl acetate, diethyl ether, t-butyl methyl ether, benzene, toluene, DMF and DMSO, and preferably water, methanol, ethanol, (n- or i-)propyl alcohol and acetonitrile.

Concrete preferable examples of the compounds expressed by the formula (1) or the formula (2) of the present invention are compounds described in the Table 1 to the Table 43, their pharmacologically permissible salts or their solvates.

TABLE 1 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

 

TABLE 2 31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

 

TABLE 3 60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

 

TABLE 4 88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

 

TABLE 5 118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

 

TABLE 6 148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

 

TABLE 7 178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

 

TABLE 8 208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

 

TABLE 9 238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

 

TABLE 10 268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

290

291

292

293

294

295

296

297

 

TABLE 11 298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

 

TABLE 12 328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

348

349

350

351

352

353

354

355

356

357

 

TABLE 13 358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

384

385

386

387

 

TABLE 14 388

389

390

391

392

393

394

395

396

397

398

399

400

401

402

403

404

405

406

407

408

409

410

411

412

413

414

415

416

417

 

TABLE 15 418

419

420

421

422

423

424

425

426

427

428

 

TABLE 16 429

430

431

432

433

434

435

436

437

438

439

440

441

442

443

444

445

446

447

448

449

450

451

452

453

454

455

456

457

458

 

TABLE 17 459

460

461

462

463

464

465

466

467

468

469

470

471

472

473

474

475

476

477

478

479

480

481

482

483

484

485

486

487

488

 

TABLE 18 489

490

491

492

493

494

495

496

497

498

499

500

501

502

503

504

505

506

507

508

509

510

511

512

513

514

515

516

517

518

 

TABLE 19 519

520

521

522

523

524

525

526

527

528

529

530

531

532

533

534

535

536

537

538

539

540

541

542

543

544

545

546

547

548

 

TABLE 20 549

550

551

552

553

554

555

556

557

558

559

560

561

562

563

564

565

566

567

568

569

570

571

572

573

574

575

576

577

578

 

TABLE 21 579

580

581

582

583

584

585

586

587

588

589

590

591

592

593

594

595

596

597

598

599

600

601

602

603

604

605

606

607

608

 

TABLE 22 609

610

611

612

613

614

615

616

617

618

619

620

621

622

623

624

625

626

627

628

629

630

631

632

633

634

635

636

637

638

 

TABLE 23 639

640

641

642

643

644

645

646

647

648

649

650

651

652

653

654

655

656

657

658

659

660

661

662

663

664

665

666

667

668

 

TABLE 24 669

670

671

672

673

674

675

676

677

678

679

680

681

682

683

684

685

686

687

688

689

690

 

TABLE 25 691

692

693

694

695

696

697

698

699

700

701

702

703

704

705

706

707

708

709

710

711

712

713

714

715

716

717

718

719

720

 

TABLE 26 721

722

723

724

725

726

727

728

729

730

731

732

733

734

735

736

737

738

739

740

741

742

743

744

745

746

747

748

749

750

 

TABLE 27 751

752

753

754

755

756

757

758

759

760

761

762

763

764

765

766

767

768

769

770

771

772

773

774

775

776

777

778

 

TABLE 28 779

780

781

782

783

784

785

786

787

788

789

790

791

792

793

794

795

796

797

798

799

800

801

802

 

TABLE 29 803

804

805

806

807

808

809

810

811

812

813

814

815

816

817

818

819

820

821

822

823

824

825

826

827

828

829

830

831

 

TABLE 30 832

833

834

835

836

837

838

839

840

841

842

843

844

845

846

847

848

849

850

851

852

853

854

855

856

857

858

859

860

861

 

TABLE 31 862

863

864

865

866

867

868

869

870

871

872

873

874

875

876

877

878

879

880

881

882

883

884

885

886

887

888

889

890

 

TABLE 32 891

892

893

894

895

896

897

898

899

900

901

902

903

904

905

906

907

908

909

910

911

912

913

914

915

916

917

918

 

TABLE 33 919

920

921

922

923

924

925

926

927

928

929

930

931

932

933

934

935

936

937

938

939

940

941

942

943

944

945

946

947

948

 

TABLE 34 949

950

951

952

953

954

955

956

957

958

959

960

961

962

963

964

965

966

967

968

969

970

971

972

973

974

975

976

977

978

979

980

 

TABLE 35 981

982

983

984

985

986

987

988

989

990

991

992

993

994

995

996

997

998

999

1000

1001

1002

1003

1004

1005

1006

1007

1008

1009

1010

 

TABLE 36 1011

1012

1013

1014

1015

1016

1017

1018

1019

1020

1021

1022

1023

1024

1025

1026

1027

1028

1029

1030

1031

1032

1033

1034

1035

1036

1037

1038

1039

1040

 

TABLE 37 1041

1042

1043

1044

1045

1046

1047

1048

1049

1050

1051

1052

1053

1054

1055

1056

1057

1058

1059

1060

1061

1062

1063

1064

1065

1066

1067

1068

1069

1070

 

TABLE 38 1071

1072

1073

1074

1075

1076

1077

1078

1079

1080

1081

1082

1083

1084

1085

1086

1087

1088

1089

1090

1091

1092

1093

1094

1095

1096

1097

1098

1099

1100

 

TABLE 39 1101

1102

1103

1104

1105

1106

1107

1108

1109

1110

1111

1112

1113

1114

1115

1116

1117

1118

1119

1120

1121

1122

1123

1124

1125

1126

1127

1128

1129

1130

 

TABLE 40 1131

1132

1133

1134

1135

1136

1137

1138

1139

1140

1141

1142

1143

1144

1145

1146

1147

1148

1149

1150

1151

1152

1153

1154

1155

1156

1157

1158

1159

1160

 

TABLE 41 1161

1162

1163

1164

1165

1166

1167

1168

1169

1170

1171

1172

1176

1181

1182

1184

1185

1186

1187

1188

1189

1190

 

TABLE 42 1191

1192

1193

1194

1195

1196

1197

1198

1199

1200

1201

1202

1203

1204

1205

1206

1207

1208

1209

1210

1211

1212

1213

1214

1215

1216

1217

1218

1219

1220

 

TABLE 43 1221

1222

1223

1224

1225

1226

1227

1228

1229

1230

1231

1232

1233

1234

1235

1236

1237

1238

1239

1240

1241

1242

1243

1244

1245

1246

 

The anthranilic acid derivative of the present invention has strong cytotoxic activity and/or IgE antibody production suppressing activity. Concretely, as for cytotoxic activity, LC50 or GI50 is 5,000 nM or less, preferably 0.05 nM to 1,000 nM, more preferably 0.05 nM to 500 nM. As for IgE antibody production suppressing activity, IC50 is 1,000 nM or less, preferably 0.05 nM to 500 nM, more preferably 0.05 M to 100 nM.

The anthranilic acid derivative of the present invention having such an excellent cytotoxic activity can be used as a therapeutic agent clinically applicable to cancer. Since the anthranilic acid derivative of the present invention further has excellent IgE antibody production suppressing activity, compounds having relatively weak cytotoxicity among the above compounds are rather suitable for the use as a preventing agent and/or therapeutic agent clinically applicable to various allergic diseases.

The derivative of the present invention expressed by the aforementioned formula (1) or formula (2) or its pharmacologically permissible salt can be produced for example according to the following scheme.

 

Namely, an aryl derivative [I] or [VI] having a group expressed by Z¹X³ or Z¹X⁴ (Z¹ is hydrogen atom, a general protecting group such as benzyl group, benzoyl group, methoxymethyl group, acetyl group or trimethylsilyl group, the group Z defined in the formula (3)-1 and the formula (3)-2 or the group R⁷ defined in the formula (5)-1 or the formula (5)-2) and a carboxylic acid group is coupled with an anthranilic acid derivative [II] under a proper condition to enable the production of the compounds [III] and [VII] from the starting compounds [I] and [VI], respectively. The group Z¹ of the produced compound [III] or [VII] is deprotected to obtain respective intermediate [IV] or [VIII] and a side chain Z is introduced into the compound [IV] to obtain the compound [V] or a side chain Z or a group R⁷ is introduced into the compound [VIII] to obtain a compound [IX]. When the group —CO₂R³ is an ester, the product can be converted as necessary into a carboxylic acid by hydrolyzing the ester of the compound [V] or [IX]. When the group Z¹ in the compound [III] or [VII] is Z or R⁷ defined before, the compound [III] or [VII] becomes the objective compound [V] or [IX], respectively, and when the group —CO₂R³ is an ester, the ester [III] and [VII] can be converted as necessary into a carboxylic acid by hydrolysis.

The definitions of the groups A, Z, X¹ to X⁴, R¹ to R⁹ and n in the above formulas are same as the definitions in the formulas (1), (2), (3)-1, (3)-2, (5)-1 and (5)-2. There is no restriction on the production process of the starting substances [I] and [VI], and these compounds can be produced by known conventional methods.

The compounds [V] and [IX] are concretely synthesizable as follows.

The condensation of the compound [I] or [VI] to the compound [II] can be roughly classified into a method through an acid halide and an activation method without passing through an acid halide and either method is principally a known method.

In the case of passing through an acid halide, the objective compounds [III] and [VII] can be produced from the compounds [I] and [II] and the compounds [VI] and [II], respectively, by treating the compound [I] or [VI] with a proper halogenation agent such as oxalyl chloride and thionyl chloride in the presence or absence of an additive such as DMF in a proper solvent (e.g. methylene chloride or tetrahydrofuran) and reacting the produced acid halide with the compound [II] in the presence or absence of a proper base (e.g. triethylamine or potassium carbonate).

In the activation method which does not go through an acid halide, the objective compounds [III] and [VII] can be produced from the compounds [I] and [II] and the compounds [VI] and [II], respectively, by activating the compound [I] or [VI] with a proper activation agent such as mixed acid anhydride, carbodnmides, imidazolation agent, halophosphoric acid esters or cyanophosphoric acid esters in a proper solvent (e.g. methylene chloride or tetrahydrofuran) and reacting the activated compound with the compound [II].

The group Z¹ in Z¹X³ of the compounds [III] and [VII] may be Z and in Z²X⁴ may be R¹ itself. When X³ is —O—, —S—, —NR²¹ or —(C═O)NR²¹ (in this case, the carbonyl group is bonded to the benzene ring or naphthalene ring in the formula (3)-1 or the formula (3)-2, and the definition of R²¹ is same as the definition in the formula (3)-1 and the formula (3)-2) or X⁴ is —O—, —S—, —NR²³— or —(C═O)NR²³ (in this case, the carbonyl group is bonded to the benzene ring or naphthalene ring in the formula (5)-1 or the formula (5)-2 and the definition of R²³ is same as the definition in the formula (5)-1 and the formula (5)-2), the compound [IV] or [VIII] can be used as an intermediate after deprotection by using a proper protecting group (for example, ethers of benzyl group, allyl group, etc., silyl ethers of t-butyldimethylsilyl group, etc., esters of benzoyl group, etc., carbonates such as allyl carbonate, etc. when X³ or X⁴ is —O—; thioethers of benzyl group, etc., thioesters of benzoyl group, etc., thiocarbonates of t-butyl carbonate, etc. when it is —S—; benzyl group, formyl group, etc. when it is —NR²¹— or —NR²³—; and t-butyldimethylsilyloxy group, methylthio group, etc. when it is —(C═O)NR²¹ or —(C═O)NR²³), and the compound [V] can be produced by introducing Z into the compound [IV] or the compound [IX] can be produced by introducing Z or R⁷ into the compound [VIII] to facilitate the development of synthesis. For example, when X³ or X⁴ in the compound [III] or [VII] is —O—, the debenzylated intermediate [IV] or [VIII] can be produced from the compound [III] or [VII] by hydrogenation by the use of benzyl group as the group Z¹. Further, the introduction of Z into the compound [IV] gives the compound [V] and the introduction of Z or R⁷ into the compound [VIII] gives the compound [IX]. In this case, R³ is preferably a C1-C4 hydrocarbon group among the groups defined in the formula (1) and the formula (2) from the viewpoint of the handling in synthesis. In other words, the compound of the formula (1) or formula (2) wherein R³ is hydrogen atom is produced preferably by introducing the group Z into the intermediate [IV] or introducing the group Z or the group R⁷ into the intermediate [VIII] and hydrolyzing the group CO₂R³ (i.e. the group R³ is a C1-C4 hydrocarbon group).

There is no particular restriction on the method for introducing the group Z of the formula (3)-1 and the formula (3)-2 or the group R⁷ of the formula (5)-1 and the formula (5)-2 into the compound [IV] or [VIII], and the introduction can be carried out for example by using a reactant ZX⁵, R⁷X⁵, etc. An alcohol and an alkyl halide are concrete examples of ZX⁶ or R⁷X⁶ when X³ and X⁴ are —O—. The objective compound [V] containing introduced group Z or the compound [IX] containing introduced group Z or R⁷ can be produced, in the case of using an alcohol as the ZX⁵ or R⁷X⁵, by using ZOH or R⁷OH, triphenyl phosphine (which may be replaced with tributyl phosphine, etc.), diethyl azodicarboxylate [which may be replaced with diisopropyl azodicarboxylate or 1,1-azobis(N,N-dimethylformamide)] and carrying out Mitsunobu synthesis or its analogous reaction in a proper solvent (e.g. N-methylmorpholine or tetrahydrofuran) at a proper temperature condition. In the case of using an alkyl halide, etc., ire. using a halogen atom as the eliminable group X⁵, the objective compound [V] or [IX] can be produced by carrying out the reaction in the presence of a proper base such as sodium hydride, potassium carbonate or triethylamine in a proper solvent (e.g. dimethylformamide, tetrahydrofuran, acetonitrile or methylene chloride) under a proper temperature condition.

When the group X³ is —NR²¹ or the group X⁴ is —NR²³, the group Z in the formula (3)-1 or the formula (3)-2 or the group R⁷ in the formula (5)-1 or the formula (5)-2 can be introduced by the above reaction similar to the case that the group X³ or X⁴ is —O—. When the group X³ or X⁴ is —S—, the compound ZX⁵ is an alkyl halide derivative, etc. In the case of synthesizing a compound containing —NH—, —NH₂—, —CO₂H, —OH, —SH, etc., in the group Z of the compound [V] or [IX] and further containing a substituent introduced into these functional groups, a compound of formula Z²X⁵ (there is no particular definition of Z², however, it is a group produced by introducing a proper protecting group into —NH, —NH₂, —CO₂H, —OH or —SH in the side chain) having proper protecting group introduced into —NH, —NH₂, —CO₂H, —OH or —SH is synthesized beforehand, the synthesized compound is made to react with the compound [IV] or [VIII] by the aforementioned method to introduce the group Z², the protecting group of —NH—, —NH₂, —CO₂H, —OH or —SH in the group Z² is removed, the product is used as an intermediate and various substituents are introduced into the intermediate to obtain the objective new compound having the group Z. When the group —CO₂R³ is an ester, it can be induced as necessary into a carboxylic acid compound by hydrolyzing the ester —CO₂R³.

Concrete example of the synthesizing process is the protection of the amino group of trans-4-aminocyclohexanol with benzyl group beforehand to obtain a dibenzyl compound, Mitsunobu reaction of the product with an intermediate [IV] or [VIII], debenzylation of the product to obtain an amino compound and the reaction with a reagent having a group to be introduced, for example, an acid chloride, sulfonyl chloride, etc., to obtain an amide compound, a sulfonamide compound, etc., as the objective compound. When the group —CO₂R³ is an ester, a carboxylic acid compound can be produced as necessary by hydrolyzing the group —CO₂R³ Also in this case, the group R³ is preferably a C1-C4 lower hydrocarbon group among the above definition in the formula (1) and the formula (2) from the viewpoint of handleability in synthesis, namely, a compound wherein R³ is hydrogen atom is preferably produced by the hydrolysis of —CO₂R³.

A compound of the formula (1) or (2) wherein X¹, X³ and X⁴ are each —(S═O)— or —(O═S═O)— or A is N→O can be produced by oxidizing a corresponding compound wherein X¹, X³ or X⁴ are S or A is N. Although there is no particular restriction on the stage for oxidizing S or N in the above case, the objective oxidized product can be produced e.g. by oxidizing the non-oxidized compound [V] or [IX] with a general oxidizing agent such as peroxide or NBS.

A compound of the formula (1) or (2) wherein X³ or X⁴ is —(C═O)— can be synthesized e.g. by introducing ZCO or R⁷CO by Friedel-Crafts reaction at an arbitrary reaction stage. As an alternative, in the case of using a compound having carboxylic acid group at a position corresponding to the X³ or X⁴ on the benzene ring or naphthalene ring of the formula (3)-1, (3)-2, (5)-1 or (5)-2, the carboxylic acid can be converted into a ketone by activating the carboxylic acid with carbodmidazole, etc., converting into an amide with N-methoxy-N-methylamine and reacting with a Grignard reagent of group Z or group R⁷ or lithium anion. When a raw material having carboxylic acid group at a position corresponding to the group X³ or X⁴ of the formula (3)-1, (3)-2, (5)-1 or (5)-2 is unavailable, a compound having methyl group, aldehyde group or —CH₂OH at the corresponding position can be converted into carboxylic acid by oxidization. A compound having cyano group at the corresponding group can be converted into carboxylic acid by the hydrolysis of the cyano group. Further, even a compound having only hydrogen atom at the corresponding position can be converted into a carboxylic acid e.g. by the carboxylation with carbon dioxide.

When the group X³ is —NR²¹(C═O) or the group X⁴ is —NR²³(C═O) (in this case, the N of —NR²¹(C═O) is bonded to the benzene ring or naphthalene ring in the formula (3)-1 or the formula (3)-2 and the N of —NR²³(C═O) is bonded to the benzene ring or naphthalene ring in the formula (5)-1 or the formula (5)-2. The definition of R²¹ is same as the one shown in the formula (3)-1 and the formula (3)-2 and that of R²³ is same as the one shown in the formula (5)-1 and the formula (5)-2.), the objective compound [V] or [IX] can be synthesized by reacting, at an arbitrary reaction stage, the compound [IV] or [VIII] with an acid chloride of the compound of the formula ZCO₂H or its activated product in the case that the group —X³H of the compound [IV] or [VIII] is —NHR²¹ or reacting the compound [VIII] with an acid chloride of the formula R⁷CO₂H or ZCO₂H or its activated product in the case that the group —X⁴H of the compound [VIII] is —NHR²³.

When the group X³ is —(C═O)NR²¹ or the group X⁴ is —(C═O)NR²³ (in this case, the carbonyl group of —(C═O)NR²¹ is bonded to the benzene ring or naphthalene ring in the formula (3)-1 or the formula (3)-2 and the carbonyl group of —(C═O)NR²³ is bonded to the benzene ring or naphthalene ring in the formula (5)-1 or the formula (5)-2. The definition of R²¹ is same as the one expressed in the formula (3)-1 and the formula (3)-2 and that of R²³ is same as the one expressed in the formula (5)-1 and the formula (5)-2.), the objective compound can be synthesized by coupling, at an arbitrary reaction stage, a corresponding amine with a compound produced by activating a carboxylic acid with carbodinimdazole or oxalyl chloride, etc., using a compound having carboxylic acid group at a position corresponding to the X³ or the X⁴ of the formula (3)-1, the formula (3)-2, the formula (5)-1 or the formula (5)-2.

When the group R⁴ is an alkyl group, the objective compound is synthesized, although there is no restriction on the synthesis method, preferably by N-alkylating an anthranilic acid derivative [II] with a general alkylation agent, e.g. an alkyl halide such as an alkyl iodide before the coupling of the derivative with a compound [I] or [VI] in the above scheme and then coupling the alkylation product with the compound [I] or [VI].

Although there is no particular restriction on the process for the synthesis of the compounds [I] and [VI] which are raw materials for the above scheme, these compounds can be synthesized with reference to the description of the International Application WO95/32943 and the International Application 97/19910 or by the following method.

In the case of n is zero, these compounds can be synthesized according to the following scheme.

 

In the above scheme, the definitions of R⁵, R⁶, R⁸, R⁹, X¹, X³, X⁴ and A are same as the definitions in the formula (1), the formula (2), the formula (3)-1, the formula (3)-2, the formula (5)-1 and the formula (5)-2. The definition of Z¹ is same as the aforementioned definition. The group R²⁶ is hydrogen atom or a C1-C4 hydrocarbon group. As shown in the above scheme, these compounds can be produced by coupling the compound [X], [XI], [XII] or [XIII] having X⁷ as a nucleophilic site with the compound [XIV] or [XVI] having a proper eliminable group such as halogen atom on X⁸ using a proper base reagent and a proper solvent, concretely, the compound [XV] can be synthesized by coupling the compound [X] or [XI] with the compound [XIV] and the compound [XVII] can be synthesized by coupling the compound [X], [XI], [XII] or [XIII] with the compound [XVI]. When the group R²⁶ is a hydrocarbon group, the compound [XV] and [XVII] can be converted into the corresponding carboxyhic acid [I] and [VI] by the hydrolysis of the ester. Concretely, it can be synthesized by the following method.

In the case of producing the compound [XV] by the reaction of the compound [X] or [XI] with the compound [XIV] and in the case that the group X¹ is —O— or —S—, the objective compound [XV] can be synthesized by reacting the compound [X] or [XI] wherein X⁷ is —OH or —SH with the compound [XIV] wherein X⁸ is F in the presence of a proper base reagent such as potassium carbonate (other examples of the reagent are sodium carbonate, potassium bicarbonate, etc.) in a proper solvent such as N,N-dimethylacetamide (other examples of the solvent are N,N-dimethylformamide, tetrahydrofuran, methylene chloride, etc.) under a proper temperature condition comprising the reaction at room temperature or under heating. In the above case, the group R²⁶ of the compound [XIV] is preferably a C1-C4 hydrocarbon group from the viewpoint of the handleability in synthesis. In other words, it is preferable to obtain the carboxylic acid [I] by the ester hydrolysis of the compound [XV].

In the case of producing the compound [XVII] by the reaction of the compound [X], [XI], [XII] or [XIII] and in the case that the group X¹ is —O— or —S—, the compound [XVII] can be synthesized by reacting the compound [X], [XI], [XII] or [XIII] wherein the group X⁷ is —OH or —SH with the compound [XVI] wherein the group X⁸ is —Cl in the presence of a proper base reagent such as sodium hydride (other examples of the reagent are potassium carbonate, sodium carbonate and potassium bicarbonate) in a proper solvent such as N,N-dimethylformamide under a proper temperature condition comprising the reaction at 0° C. or under heating. Also in the above case, the group R²⁶ of the compound [XVI] is preferably a C1-C4 hydrocarbon group from the viewpoint of the handleability in synthesis. In other words, it is preferable to obtain the carboxylic acid [VI] by the ester hydrolysis of the compound [XVII].

In the case of n is 1, these compounds can be synthesized according to the following scheme.

 

In the above scheme, the definitions of R⁵, R⁶, R⁸, R⁹, X¹, X³, X⁴ and A are same as the definitions in the formula (1), the formula (2), the formula (3)-1, the formula (3)-2, the formula (5)-1 and the formula (5)-2, and the definition of Z¹ is same as aforementioned definition. As shown in the above scheme, these compound can be produced by coupling the compound [X], [XI], [XII] or [XIII] having X⁷ as a nucleophilic site with the compound [XVIII] or [XXI] having a proper eliminable group such as halogen atom on the group X⁸ using a proper base reagent and a proper solvent to synthesize the compound [XIX] from the compound [α]or [XI] or synthesize the compound [XXII] from the compound [X], [XI], [XII] or [XIII] and the product is subjected to rearrangement reaction to synthesize the thioamide [XX] from the compound [XIX] or synthesize the compound [XXIII] from the compound [XXII]. Furthermore, the products [XX] and [XXIII] can be converted into the compounds [I] and [VI] by hydrolysis. Concretely, the synthesis can be performed as follows.

In the case of producing the compound [XIX] by the reaction of the compound [X] or [XI] with the compound [XVIII] and in the case that the group X¹ is —O— or —S—, the objective compound [XIX] can be synthesized by reacting the compound [X] or [XI] wherein X⁷ is —OH or —SH with the compound [XVIII] wherein X⁸ is —F in the presence of a proper base reagent such as potassium carbonate (other examples of the reagent are sodium carbonate, potassium bicarbonate and sodium hydride) in a proper solvent such as N,N-dimethylacetamide under a proper temperature condition comprising the reaction at room temperature or under heating. The product can be converted into the compound [I] by heating in the presence of S and morpholine to effect the rearrangement reaction and hydrolyzing the resultant thioamide [XX].

In the case of producing the compound [XXII] by the reaction of the compound [X], [XI], [XII] or [XIII] and in the case that the group X¹ is —O— or —S—, the compound [XXII] can be synthesized by reacting the compound [X], [XI], [XII] or [XIII] wherein the group X⁷ is —OH or —SH with the compound [XXI] wherein the group X⁸ is —Cl in the presence of a proper base reagent such as sodium hydride (other examples of the reagent are potassium carbonate, sodium carbonate and potassium bicarbonate) in a proper solvent such as N,N-dimethylformamide under a proper temperature condition comprising the reaction at 0° C. or under heating. The product can be converted into the compound [VI] by heating in the presence of S and morpholine to effect the rearrangement reaction and hydrolyzing the resultant thioamide [XXIII].

Although there is no particular restriction on the process for the synthesis of the compounds [I] and [VI] wherein n is 2 or 3 and X¹ is —O— or —S—, these compounds can be synthesized with reference to a coupling method described in the paper of Journal of Medicinal Chemistry vol. 40, no. 4, sections 395-407 (1997) or similar methods.

Similarly, the compounds [I] and [VI] wherein n is 0 or 3 and X¹ is —(C═O)— or —CH₂— can be synthesized, although there is no restriction on the process, with reference to a coupling method described in the paper of Journal of Medicinal Chemistry vol. 40, no. 4, sections 395-407 (1997) or similar methods.

The anthranilic acid derivative of the present invention and its pharmacologically permissible salt can be administered by peroral means or parenteral means such as intravenous injection, subcutaneous injection, intramuscular injection, transcutaneous administration, rectal infusion, nasal administration, eye instillation or by inhalation.

The form of the oral administration drug is, for example, tablet, pill, granule, powder, liquid, suspension, syrup or capsule.

A tablet can be formed by conventional method using an excipient such as lactose, starch and crystalline cellulose, a binder such as carboxymethylcellulose, methylcellulose and polyvinylpyrrolidone, a disintegrant such as sodium alginate, sodium bicarbonate and sodium laurylsulfate; etc.

A pill, granule and powder are also formable by conventional method using the above excipients, etc.

A liquid agent, suspension and syrup can be formed by conventional method using a glycerol ester such as tricaprylin and triacetin; an alcohol such as ethanol; water; a vegetable oil such as corn oil, cottonseed oil, coconut oil, almond oil, peanut oil and olive oil; etc.

A capsule can be formed by filling a granule, powder or liquid agent into a capsule made of gelatin, etc.

The agent for intravenous, subcutaneous or intramuscular administration is, for example, an injection composed of an aseptic aqueous or non-aqueous solution agent. The aqueous solution agent is produced e.g. by using physiological salt solution. The non-aqueous solution agent is produced e.g. by using propylene glycol, polyethylene glycol, a vegetable oil such as olive oil, an injectable organic ester such as ethyl oleate, etc. These drugs may be incorporated as necessary with isotropic agent, antiseptic agent, wetting agent, emulsifying agent, dispersing agent, stabilizing agent, etc., and asepticized by proper treatments such as filtration through a bacteria-retaining filter, compounding of a disinfectant, heating treatment, irradiation treatment, etc. As an alternative, it can be used by preparing an aseptic solid preparation and dissolving the agent in aseptic water or an aseptic solvent for injection immediately before use.

The agent for percutaneous administration is an ointment agent, a cream agent, etc. These agents can be produced by conventional method using an oil and fat such as castor oil or olive oil or petrolatum, etc., for an ointment agent and a fatty oil, diethylene glycol, an emulsifier such as sorbitan monofatty acid ester, etc., for a cream agent.

A conventional suppository such as gelatin soft capsule is used for the rectal administration.

The preparation for transnasal administration is supplied in the form of a liquid or powdery composition. The base for the liquid agent is water, salt solution, phosphate buffer solution, acetate buffer solution, etc., and the agent may further contain a surfactant, an antioxidant, a stabilizer, a preservative and a thickening agent. The base for the powdery agent is preferably a water-absorbing material, for example, easily water-soluble polyacrylic acid salts such as sodium polyacrylate, potassium polyacrylate and ammonium polyacrylate; cellulose lower alkyl ethers such as methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and carboxymethylcellulose sodium; polyethylene glycol polyvinylpyrrolidone, amylose, pullullan etc.; celluloses such as a scarcely water-soluble crystalline cellulose, a cellulose and crosslinked carboxymethylcellulose sodium; starches such as hydroxypropyl starch, carboxymethyl starch, crosslinked starch, amylose, amylopectin and pectin; proteins such as gelatin, casein and casein sodium; gums such as gum arabic, tragacanth gum and glucomannan; crosslinked vinyl polymers such as polyvinylpolypyrrolidone, crosslinked polyacrylic acid and its salt, crosslinked polyvinyl alcohol and polyhydroxyethyl methacrylate; etc., or their mixture. The powdery agent may be incorporated further with an antioxidant, a colorant, a preservative, an antiseptic agent, a decay modifying agent, etc. Such liquid agent and powdery agent can be administered e.g. by using a spraying tool.

The eye instillation agent is an aqueous or non-aqueous instillation. The aqueous instillation can be produced by using sterilized pure water, physiological salt solution or proper aqueous solvent as the solvent, and includes an aqueous eye drop produced by using only a sterilized pure water as the solvent; a viscous eye drop added with a thickening agent such as carboxymethylcellulose, methylcellulose, hydroxypropylcellulose and polyvinylpyrrolidone; an aqueous suspension eye drop added with a surfactant or a suspension agent such as, a polymer thickener; a solubilized eye drop added with a solubilizing agent such as a nonionic surfactant; etc. The non-aqueous instillation uses a non-aqueous solvent for injection as the solvent and includes a non-aqueous eye drop produced by using vegetable oil, liquid paraffin, mineral oil, propylene glycol, etc.; a non-aqueous suspension eye drop produced by using a thixotropic colloid such as aluminum monostearate as a suspension agent; etc. These preparations may be incorporated as necessary with an isotonic agent, a preservative, a buffer agent, an emulsifier, a stabilizing agent, etc., or asepticized by proper treatments such as filtration through a bacteria-retaining filter, compounding of a disinfectant, heating treatment, irradiation treatment, etc. As an alternative, it can be used by preparing an aseptic solid preparation and dissolving or suspending the agent in a proper aseptic solution immediately before use.

The dosage form for the administration to the eye other than an ophthalmic instillation is an eye ointment formed by using petrolatum, etc.; an application liquid produced by using dilute iodine tincture, zinc sulfate solution, methyl chloride rosaniline liquid, etc.; a scattering agent to directly apply fine powder of active component; an insertion agent produced by compounding or impregnating an active component in a proper base or a material and used by inserting into the eyelid, etc.

A solution or suspension of an active component and a conventional excipient for medicine is used for the inhalation, for example, in the form of an aerosol spray for inhalation. As an alternative, an active component having dried powdery form is administered by an inhalator or other device to enable the direct contact of the active component with the lung.

The administration dose of the compound of the present invention depends upon the kind of disease, administration path, condition, age, sex, body weight, etc., of the patient, etc. It is about 0.1 to 1,000 mg/day/head, preferably 1 to 300 mg/day/head in oral administration and about 0.1 to 100 mg/day/head, preferably 0.1 to 30 mg/day/head in parenteral administration such as intravenous, subcutaneous, intramuscular, percutaneous, rectal or nasal administration, ophthalmic instillation and inhalation, and the drug is prepared preferably to satisfy the above condition.

In the case of using the compound of the present invention as a preventing agent, such preparations may be administered beforehand according to each symptom by the administration method known as a method for the administration of preventing agent.

As shown in the following Examples, the anthranilic acid derivative of the present invention is effective for suppressing the highly proliferative L929 cell at a low concentration. Since the derivative is also effective for suppressing the proliferation of various other human cancer cells at a low concentration, it is extremely useful as a carcinostatic agent. Furthermore, as shown in the following Examples, the derivative also suppresses the production of IgE antibody from human lymphocyte by an antigen non-specific stimulation (IL-4+IL-10 (interleukin 10)+antiCD40Ab (anti-CD40 antibody)). Accordingly, the anthranilic acid derivative of the present invention is useful also as a preventive and/or therapeutic agent for allergic diseases caused by the production of IgE antibody such as bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, anaphylactic shock, mite allergy, pollinosis, food allergy, urticaria, ulcerative colitis, eosinophilic gastroenteritis and drug-induced rash.

EXAMPLES

The present invention is explained concretely by the following Reference Examples and Examples. The experiment was performed on the following group of compounds, however, the present invention is not restricted by these Examples. The ¹H-NMR peaks originated from carboxylic acid, hydroxyl group, amine or amide were sometimes unobservable. Although it is not particularly described, the amine compound may take the form of hydrochloride.

When the following Reference Example or Example contains the sentence of “the following compound was synthesized by a similar method using the corresponding substrate”, the used reagent was synthesized by the use of a substrate analogized from the product. In the case that the judgement by analogy was difficult, the substrate was clearly described in some Examples. The reaction temperature, the reaction time and the purification method are different to an extent among these reactions.

Reference Example 1 Synthesis of 1-(4-(6-benzyloxy-2-naphthyloxy)phenyl)ethan-1-one

 

4-Fluoroacetophenone (969 μl, 8.00 mmol) was added to dry N,N-dimethylacetamide (12 ml) solution of 6-benzyloxy-2-naphthol (500 mg, 2.00 mmol) and potassium carbonate (553 mg, 4.00 mmol) in nitrogen atmosphere and stirred at 150° C. for 5 hours. After completing the reaction, 10% citric acid was added to the reaction liquid, extracted with methylene chloride, washed with water, dried with magnesium sulfate and concentrated. The obtained residue was purified by silica gel chromatography to obtain the subject compound (707 mg, 1.92 mmol). The result of ¹H-NMR was consistent with the above structure.

Yield: 96%.

¹H-NMR (CDCl₃); δ 7.94 (d, 2H, J=8.88 Hz), 7.76 (d, 1H, J=8.91 Hz), 7.68 (d, 1H, J=9.88 Hz), 7.51-7.19 (m, 9H), 7.02 (d, 2H, J=8.91 Hz), 5.19 (s, 2H), 2.57 (s, 3H).

Reference Example 2

The following compounds were synthesized by a method similar to the Reference Example 1 using substrates corresponding to respective compounds. The results of ¹H-NMR were consistent with the above structures.

1-(4-(4-Benzyloxyphenoxy)phenyl)ethan-1-one

Yield: 73%.

¹H-NMR (CDCl₃); δ 2.56 (s, 3H), 5.07 (s, 2H), 6.97 (m, 6H), 7.42 (m, 5H), 7.91 (m, 2H).

4-(4-Benzyloxyphenyloxy)benzoic acid methyl ester

Yield: 55%.

¹H-NMR (CDCl₃); δ 7.97 (d, 2H, J=8.90 Hz), 7.31-7.46 (m, 5H), 7.00 (s, 4H), 6.93 (d, 2H, J=8.90 Hz), 5.07 (s, 2H), 3.89 (s, 3H).

In this case, 4-fluorobenzoic acid methyl ester was used in place of 4-fluoroacetophenone.

Reference Example 3 Synthesis of 1-(moroholin-4-yl)-2-(4-(6-benzyloxyphenoxy-2-naphthyloxy)phenyl)ethane-1-thione

 

The 1-(4-(6-benzyloxy-2-naphthyloxy)phenyl)ethan-1-one (3.6 g, 9.77 mmol) obtained by the Reference Example 1 was dissolved in morpholine (15 ml) in nitrogen atmosphere, added with sulfur (1.57 g, 48.8 mmol) and stirred at 120° C. for 18 hours. After completing the reaction, methanol was added to the reaction liquid and the formed precipitate was filtered to obtain the subject compound (3.73 g, 7.94 mmol) as the precipitate. The result of ¹H-NMR was consistent with the above structure.

Yield: 81%.

¹H-NMR (CDCl₃); δ 7.72 (d, 1H, J=8.91 Hz), 7.63 (d, 1H, J=9.88 Hz), 7.50-7.18 (m, 11H), 6.99 (d, 2H, J=8.59 Hz), 5.18 (s, 2H), 4.36 (t, 2H, J=4.94 Hz), 4.33 (s, 2H), 3.76 (t, 2H, J=4.78 Hz), 3.67 (t, 2H, J=4.94 Hz), 3.46 (t, 2H, J=4.78 Hz).

Reference Example 4

The following compound was synthesized by a method similar to the Reference Example 3 using the corresponding substrate. The result of ¹H-NMR was consistent with the structure.

1-(Moroholin-4-yl)-2-(4-(4-benzyloxy)phenoxy)phenyl)ethane-1-thione.

Yield: 84%.

¹H-NMR (CDCl₃); δ 7.23-7.46 (m, 7H), 6.96 (m, 6H), 5.05 (s, 2H), 4.34 (m, 2H), 4.30 (s, 2H), 3.74 (m, 2H), 3.64 (m, 2H), 3.45 (m, 2H).

Reference Example 5 Synthesis of 4-(6-benzyloxy-2-naphthoxy)phenylacetic acid

 

An aqueous solution (10 ml) of 50% sodium hydroxide was added to 70% ethanol solution (50 ml) of the 1-(morpholin-4-yl)-2-(4-(6-benzyloxyphenoxy-2-naphthyloxy)phenyl)-ethane-thione (3.73 g, 7.94 mmol) obtained by the Reference Example 3 and the mixture was stirred at 100° C. for a night. After completing the reaction, the reaction liquid was added with 6N hydrochloric acid to adjust the pH to about 2, extracted with ethyl acetate, washed with water, dried with magnesium sulfate and concentrated. The obtained crude product was recrystallized from acetonitrile to obtain the subject compound (2.10 g, 5.46 mmol). The result of ¹H-NMR was consistent with the above structure.

Yield: 69%.

¹H-NMR (DMSO-d₆); δ 12.38 (br, 1H), 7.93 (d, 1H, J=8.91 Hz), 7.86 (d, 1H, J=8.88 Hz), 7.61-7.24 (m, 11H), 7.08 (d, 2H, J=8.48 Hz), 5.30 (s, 2H), 3.65 (s, 2H).

Reference Example 6

The following compound was synthesized by a method similar to the Reference Example 5 using a corresponding substrate. The result of ¹H-NMR was consistent with the structure.

4-(4-Benzyloxyphenoxy)phenylacetic acid

Yield: 86%.

¹H-NMR (DMSO-d₆); δ 12.12 (s, 1H), 7.31-7.14 (m, 5H), 7.06 (d, 2H, J=8.41 Hz), 6.85 (m, 4H), 6.70 (d, 2H, J=8.41 Hz), 4.92 (s, 2H), 3.36 (s, 2H).

Reference Example 7 Synthesis of 4-(6-benzyloxy-2-naphthyloxy)benzoic acid

 

4-(6-Benzyloxy-2-naphthyloxy)benzoic acid ethyl ester (10.6 g, 26.2 mmol) was dissolved in a 2:1 mixture of THF and methanol (150 ml), added with 4N lithium hydroxide (33 ml) and stirred at room temperature. After completing the reaction, the reaction liquid was adjusted to pH 2 or thereabout with 1N hydrochloric acid, extracted with ethyl acetate, washed with water, dried with magnesium sulfate and concentrated to obtain the subject compound (8.70 g, 23.4 mmol). The result of ¹H-NMR was consistent with the above structure.

Yield: 88%.

¹H-NMR (DMSO-d₆); δ 12.79 (brs, 1H), 7.94 (d, 2H, J=8.91 Hz), 7.90 (d, 1H, J=8.91 Hz), 7.82 (d, 1H, J=8.91 Hz), 7.56-7.25 (m, 9H), 7.05 (d, 2H, J=8.74 Hz), 5.23 (s, 2H).

Reference Example 8

The following compound was synthesized by a method similar to the Reference Example 7 using a corresponding substrate. The result of ¹H-NMR was consistent with the structure.

4-(4-Benzyloxyphenyloxy)benzoic acid

Yield: 89%.

¹H-NMR (DMSO-d₆); δ 7.90 (d, 2H, J=8.91 Hz), 7.47-7.30 (m, 5H), 7.08 (s, 4H), 6.95 (d, 2H, J=8.91 Hz), 5.10 (s, 2H).

In this case, the methyl ester of the subject compound was used as the substrate.

Reference Example 9 Synthesis of 6-(4-benzyloxyphenoxy)-3-acetylpyridine

 

Dried DMF solution (50 ml) of sodium hydride (60% in oil, 7.24 g, 181 mmol) was cooled with ice in nitrogen atmosphere, dried DMF solution (50 ml) of hydroquinone monobenzyl ether (36.2 g, 181 mmol) was dropped into the above solution spending 10 minutes under ice cooling and the mixture was stirred for 1.5 hours under ice cooling. Dried DMF solution (110 ml) of 6-chloro-3-acetylpyridine (26.7 g, 172 mmol) was dropped into the above mixture spending 15 minutes and stirred for 2 hours under ice cooling. After completing the reaction, the reaction liquid was acidified with 6N hydrochloric acid, added with water, extracted with ethyl acetate, washed with water (400 ml×3), dried with magnesium sulfate and concentrated. The residue was recrystallized from 2-propanol (300 ml) to obtain the subject compound (43.3 g, 136 mmol). The result of ¹H-NMR was consistent with the above structure.

Yield: 75%.

¹H-NMR (CDCl₃); δ 8.76 (d, 1H, J=2.64 Hz), 8.24 (dd, 1H, J=2.64, 8.58 Hz), 7.46-7.31 (m, 5H), 7.10-7.00 (m, 4H), 6.94 (d, 1H, J=8.58 Hz), 5.08 (s, 2H), 2.56 (s, 3H).

Reference Example 10

The following compounds were synthesized by a method similar to the Reference Example 9 using corresponding substrates. The results of ¹H-NMR were consistent with the structures.

6-(6-Benzyloxy-2-naphthyloxy)-3-acetylpyridine

Yield: 26%.

¹H-NMR (CDCl₃); δ 2.57 (s, 3H), 5.20 (s, 2H), 7.01 (d, 1H, J=8.78 Hz), 7.79-7.14 (m, 11H), 8.27 (dd, 1H, J=2.44 Hz, 6.10 Hz), 8.76 (d, 1H, J=2.44 Hz).

6-(4-Benzyloxyphenylthio)pyridine-3-carboxylic acid methyl ester

Yield: 81%.

¹H-NMR (CDCl₃); δ 8.81 (d, 1H, J=2.64 Hz), 8.25 (dd, 1H, J=2.31, 8.58 Hz), 7.46-7.31 (m, 5H), 7.08 (d, 2H, J=8.90 Hz), 7.02 (d, 2H, J=9.24 Hz), 6.90 (d, 1H, J=8.58 Hz), 5.07 (s, 2H), 3.91 (s, 3H).

In this case, 6-chloro-nicotinic acid methyl ester was used as the substrate in place of 6-chloro-3-acetylpyridine. Similar substrates were used in the synthesis of the following carboxylic acid methyl esters of the Reference Example 10.

6-(4-Benzyloxyphenylthio)pyridine-3-carboxylic acid methyl ester

Yield: 49%.

¹H-NMR (CDCl₃); δ 8.81 (d, 1H, J=2.63 Hz), 8.27 (dd, 1H, J=2.31, 8.58 Hz), 7.55-7.16 (m, 6H), 7.05 (d, 2H, J=8.91 Hz), 6.92 (d, 1H, J=7.57 Hz), 6.71 (d, 1H, J=8.58 Hz), 4.11 (s, 2H), 3.92 (s, 3H).

6-(4-(1-Ethylpropylthio)phenoxy)pyridine-3-carboxylic acid methyl ester

Yield: 80%.

¹H-NMR (CDCl₃); δ 8.83 (d, 1H, J=2.31 Hz), 8.28 (dd, 1H, J=1.97, 8.24 Hz), 7.45 (d, 2H, J=8.25 Hz), 7.08 (d, 2H, J=8.24 Hz), 6.94 (d, 1H, J=8.57 Hz), 3.92 (s, 3H), 2.96 (m, 1H), 1.63 (m, 4H), 1.03 (t, 6H, J=7.26 Hz).

6-(2-Methyl-4-benzyloxyphenoxy)pyridine-3-carboxylic acid methyl ester

Yield: 58%.

¹H-NMR (CDCl₆); δ 8.81 (d, 1H, J=2.31 Hz), 8.25 (dd, 1H, J=2.31, 8.91 Hz), 7.47-7.31 (m, 5H), 6.99 (d, 1H, J=8.91 Hz), 6.91-6.83 (m, 3H), 5.05 (s, 2H), 3.91 (s, 3H), 2.12 (s, 3H).

6-(3-Methyl-4-benzyloxyphenoxy)pyridine-3-carboxylic acid methyl ester

Yield: 51%.

¹H-NMR (CDCl₃); δ 8.82 (dd, 1H, J=0.66, 2.31 Hz), 8.25 (dd, 1H, J=2.31, 8.58 Hz), 7.47-7.31 (m, 5H), 6.96-6.87 (m, 4H), 5.08 (s, 2H), 3.91 (s, 3H), 2.29 (s, 3H).

Reference Example 11 Synthesis of 6-(4-benzyloxyphenoxy)pyridine-3-carboxylic acid

 

A THF-MeOH (2/1) solution (750 ml) of 6-(4-benzyloxyphenoxy)pyridine-3-carboxylic acid methyl ester (78.6 g, 234 mmol) obtained by the Reference Example 10 was added with 4N-lithium hydroxide solution (87.8 ml, 351 mmol) at room temperature (inner temperature: 15-20° C.) and stirred at room temperature (20-30° C.) for 4 hours. After completing the reaction, the reaction liquid was added with 10% aqueous solution of citric acid (600 ml) (inner temperature: 20-30° C.) to adjust the pH to about 4. The product was extracted with ethyl acetate (500 ml×3), washed with water (500 ml×1), dried with magnesium sulfate and concentrated. The residue was recrystallized from isopropanol (90 ml) to obtain the subject compound (59.9 g, 18.6 mmol). The result of ¹H-NMR was consistent with the above structure.

Yield: 80%.

¹H-NMR (DMSO-d₆); δ 13.14 (br, 1H), 8.65 (d, 1H, J=2.31 Hz), 8.26 (dd, 1H, J=2.31, 8.58 Hz), 7.48-7.31 (m, 5H), 7.13-7.03 (m, 5H), 5.12 (s, 2H).

Reference Example 12

The following compounds were synthesized by a method similar to the Reference Example 11 using corresponding substrates. The results of ¹H-NMR were consistent with the structures.

6-(4-Benzyloxyphenylthio)pyridine-3-carboxylic acid

Yield: 94%.

¹H-NMR (DMSO-d₆); δ 13.17 (br, 1H), 8.65 (d, 1H, J=2.31 Hz), 8.28 (dd, 1H, J=2.30, 8.57 Hz), 7.40-7.21 (m, 7H), 7.13-7.07 (m, 3H), 4.24 (s, 2H).

6-(4-(1-Ethylpropylthio)phenoxy)pyridine-3-carboxylic acid

Yield: 79%.

¹H-NMR (CDCl₃); δ 8.90 (d, 1H, J=2.30 Hz), 8.33 (dd, 1H, J=2.31, 8.25 Hz), 7.45 (d, 2H, J=8.25 Hz), 7.09 (d, 2H, J=7.91 Hz), 6.97 (d, 1H, J=8.91 Hz), 2.96 (m, 1H), 1.63 (m, 4H), 1.02 (t, 6H, J=7.26 Hz).

6-(2-Methyl-4-benzyloxyphenoxy)pyridine-3-carboxylic acid

Yield: 100%.

¹H-NMR (DMSO-d₆); δ 8.59 (d, 1H, 1.98 Hz), 8.23 (dd, 1H, J=1.98, 8.57 Hz), 7.48-7.31 (m, 5H), 7.01-6.98 (m, 2H), 6.92 (d, 1H, J=8.57 Hz), 6.87 (dd, 1H, J=2.97, 8.58 Hz), 5.10 (s, 2H), 2.02 (s, 3H).

6-(3-Methyl-4-benzyloxyphenoxy)pyridine-3-carboxylic acid

Yield: 100%.

¹H-NMR (DMSO-d₆); δ 8.61 (d, 1H, J=1.98 Hz), 8.22 (dd, 1H, J=1.98, 8.25 Hz), 7.50-7.31 (m, 5H), 7.05-6.98 (m, 4H), 5.13 (s, 2H), 2.21 (s, 3H).

Reference Example 13 Synthesis of N-methoxy-N-methyl(6-(4-benzyloxyphenoxy)-3-pyridyl)formamide

 

Dried THF solution (300 ml) of 6-(4-benzyloxyphenoxy)pyridine-3-carboxylic acid (58.1 g, 181 mmol) obtained by the Reference Example 11 was cooled with ice (inner temperature 3° C.) in nitrogen atmosphere, oxalyl chloride (17.4 ml, 199 mmol) was dropped into the solution (inner temperature 3-7° C.) spending 7 minutes, and the mixture was added with DMF (3 ml) and stirred for 1 hour under ice cooling or at room temperature (3 to 20° C.). The reaction liquid was concentrated and dried by evacuating with a vacuum pump. The residual THF solution (300 ml) was cooled with ice (inner temperature 3° C.) in nitrogen atmosphere, N,O-dimethylhydroxylamine hydrochloride (21.2 g, 217 mmol) was added thereto, triethylamine (60 ml, 434 mmol) was dropped into the mixture (inner temperature 5-8° C.) and stirred over a night under ice cooling to room temperature (7-20° C.). After completing the reaction, the reaction liquid was added with water (400 ml), extracted with ethyl acetate (400 ml×3), washed with water (400 ml×3), dried with magnesium sulfate and concentrated. The residue was purified by silica gel chromatography to obtain the subject compound (54 g, 148 mmol). The result of ¹H-NMR was consistent with the above structure.

Yield: 82%.

¹H-NMR (CDCl₃); δ 8.63 (dd, 1H, J=0.66, 2.31 Hz), 8.08 (dd, 1H, J=2.31, 8.58 Hz), 7.47-7.30 (m, 5H), 7.11-6.94 (m, 4H), 6.90 (dd, 1H, J=0.66, 8.58 Hz), 5.07 (s, 2H), 3.57 (s, 3H), 3.37 (s, 3H).

Reference Example 14

The following compounds were synthesized by a method similar to the Reference Example 13 using corresponding substrates. The results of ¹H-NMR were consistent with the structures.

N-Methoxy-N-methyl(6-(4-benzyloxyphenylthio)-3-pyridyl)formamide

Yield: 91%.

¹H-NMR (CDCl₃); δ 8.63 (d, 1H, J=2.31 Hz), 8.10 (dd, 1H, J=2.31, 8.58 Hz), 7.65-7.21 (m, 6H), 7.09-7.02 (m, 3H), 6.92 (d, 1H, J=8.57 Hz), 4.11 (s, 2H), 3.57 (s, 3H), 3.38 (s, 3H).

N-Methoxy-N-methyl(6-(4-(1-ethylpropyllthio)phenoxy)-3-pyridyl)formamide

Yield: 85%.

¹H-NMR (CDCl₃); δ 8.64 (d, 1H, J=2.31 Hz), 8.11 (dd, 1H, J=2.31, 8.58 Hz), 7.45 (d, 2H, J=8.58 Hz), 7.09 (d, 2H, J=8.57 Hz), 6.93 (d, 1H, J=8.57 Hz), 3.58 (s, 3H), 3.38 (s, 3H), 2.95 (m, 1H), 1.62 (m, 4H), 1.02 (t, 6H, J=7.26 Hz).

N-Methoxy-N-methyl(6-(2-methyl-4-benzyloxyphenoxy)-3-pyridyl)formamide

Yield: 72%.

¹H-NMR (CDCl₃); δ 8.63 (d, 1H, J=2.31 Hz), 8.08 (ddd, 1H, J=0.66, 2.31, 8.58 Hz), 7.47-7.33 (m, 5H), 7.00 (d, 1H, J=8.58 Hz), 6.91-6.83 (m, 3H), 5.05 (s, 2H), 3.58 (s, 3H), 3.37 (s, 3H), 2.13 (s, 3H).

N-Methoxy-N-methyl(6-(3-methyl-4-benzyloxyphenoxy)-3-pyridyl)formamide

Yield: 66%.

¹H-NMR (CDCl₃); δ 8.64 (d, 1H, J=2.31 Hz), 8.07 (dd, 1H, J=2.31, 8.58 Hz), 7.47-7.33 (m, 5H), 6.97-6.87 (4H), 5.09 (s, 2H), 3.58 (s, 3H), 3.37 (s, 3H), 2.30 (s, 3H).

Reference Example 15 Synthesis of 6-(4-benzyloxyphenoxy)-3-acetylpyridine

 

Dried THF solution (250 ml) of N-methyl-N-methoxy(6-(4-benzyloxyphenoxy)-3-pyridyl)formamide (53.3 g, 147 mmol) obtained by the Reference Example 13 was cooled in a bath of −78° C. (inner temperature −70° C.) in nitrogen atmosphere, methyllithium (1.03 M/Et20, 171 ml, 176 mmol) was dropped into the solution spending 25 minutes (inner temperature −70 to −55° C.) and the mixture was stirred in a bath of −78° C. for 1 hour inner temperature −70 to −55° C.). After completing the reaction, the reaction liquid was added with methanol (20 ml) in cooled state and stirred for 3 minutes. The cooling bath was removed and saturated aqueous solution of ammonium chloride (300 ml) was added to the liquid. The product was extracted with ethyl acetate (200 ml×3), washed with water (200 ml×1), dried with magnesium sulfate and concentrated. The residue was recrystallized from isopropanol (300 ml) to obtain the subject compound (41.9 g, 131 mmol). The result of ¹H-NMR was consistent with the above structure.

Yield: 89%.

¹H-NMR (CDCl₃); δ 8.76 (d, 1H, J=2.64 Hz), 8.24 (dd, 1H, J=2.64, 8.58 Hz), 7.46-7.31 (<m, 5H), 7.10-7.00 (m, 4H), 6.94 (d, 1H, J=8.58 Hz), 5.08 (s, 2H), 2.56 (s, 3H).

Reference Example 16

The following compounds were synthesized by a method similar to the Reference Example 15 using corresponding substrates. The results of ¹H-NMR were consistent with the structures.

6-(4-Benzyloxyphenylthio)-3-acetylpyridine

Yield: 77%.

¹H-NMR (CDCl₃); δ 8.75 (d, 1H, J=2.30 Hz), 8.26 (dd, 1H, J=2.31, 8.58 Hz), 7.37-7.21 (m, 7H), 7.06 (d, 2H, J=8.91 Hz), 6.96 (d, 1H, J=8.58 Hz), 4.12 (s, 2H), 2.57 (s, 3H).

6-(4-(1-Ethylpropylthio)phenoxy)-3-acetylpyridine

Yield: 97%.

¹H-NMR (CDCl₃); δ 8.77 (d, 1H, J=2.64 Hz), 8.26 (dd, 1H, J=2.31, 8.91 Hz), 7.45 (d, 2H, J=8.58 Hz), 7.08 (d, 2H, J=8.24 Hz), 6.97 (d, 1H, J=8.58 Hz), 2.96 (m, 1H), 2.57 (s, 3H), 1.63 (m, 4H), 1.03 (t, 6H, J=7.26 Hz).

6-(2-Methyl-4-benzyloxyphenoxy) 3-acetylpyridine

Yield: 100%.

¹H-NMR (CDCl₃); δ 8.75 (d, 1H, J=2.30 Hz), 8.24 (dd, 1H, J=2.30, 8.58 Hz), 7.47-7.31 (m, 5H), 6.99 (d, 1H, J=8.58 Hz), 6.94-6.83 (m, 4H), 5.05 (s, 2H), 2.56 (s, 3H), 2.12 (s, 3H).

6-(3-Methyl-4-benzyoxyphenoxy)-3-acetylpyridine

Yield: 100%.

¹H-NMR (CDCl₃); δ 8.76 (d, 1H, J=2.31 Hz), 8.23 (dd, 1H, J=2.31, 8.58 Hz), 7.47-7.33 (m, 5H), 6.97-6.91 (m, 4H), 5.09 (s, 2H), 2.56 (s, 3H), 2.30 (s, 3H).

Reference Example 17 Synthesis of 1-(morpholin-4-yl)-2-(6-(4-benzyloxyphenoxy)-3-pyridyl)ethane-1-thione

 

Sulfur (8.21 g, 256 mmol) was added to a morpholine solution (200 ml) of 6-(4-benzyloxyphenoxy)-3-acetylpyridine (40.8 g, 128 mmol) obtained by the Reference Example 9 in nitrogen atmosphere and stirred for 5 hours in a bath of 120° C. After completing the reaction, the reaction liquid was concentrated and purified by silica gel chromatography to obtain the subject compound (30.6 g, 73 mmol). The result of ¹H-NMR was consistent with the above structure.

Yield: 57%.

¹H-NMR (CDCl₃); δ 8.03 (d, 1H, J=2.64 Hz), 7.78 (dd, 1H, J=2.64, 8.58 Hz), 7.45-7.30 (m, 5H), 7.08-6.98 (m, 4H), 6.86 (d, 1H, J=8.58 Hz), 5.06 (s, 2H), 4.33 (dd, 2H, J=4.94, 4.95 Hz), 4.24 (s, 2H), 3.75 (dd, 2H, J=4.62, 5.28 Hz), 3.67 (dd, 2H, J=4.29, 5.28 Hz), 3.51 (dd, 2H, J=4.29, 5.28 Hz).

Reference Example 18

The following compounds were synthesized by a method similar to the Reference Example 17 using corresponding substrates. The results of ¹H-NMR were consistent with the structures.

1-(Morpholin-4-yl)-2-(6-(6-benzyloxy-2-naphthyloxy)-3-pyridyl)ethane-1-thione

Yield: 45%.

¹H-NMR (CDCl₃); δ 3.53 (m, 2H, J=2.64 Hz), 3.69 (m, 2H), 3.76 (m, 2H), 4.25 (s, 2H), 4.34 (m, 2H), 5.19 (s, 2H), 6.94 (d, 1H, J=8.58 Hz), 7.22-7.84 (m, 12H), 8.05 (d, 1H, J=2.48 Hz).

2-(6-(4-(1-Ethylpropylthio)phenoxy)-3-pyridyl)-1-(morpholin-4-yl)ethane-1-thione

Yield: quant.

¹H-NMR (CDCl₃); δ 8.06 (d, 1H, J=2.31 Hz), 7.81 (dd, 1H, J=2.64, 8.58 Hz), 7.42 (d, 2H, J=8.58 Hz), 7.05 (d, 2H, J=8.58 Hz), 6.90 (d, 1H, J=8.58 Hz), 4.33 (m, 2H), 3.76 (m, 2H), 3.74 (s, 2H), 3.67 (m, 2H), 3.52 (m, 2H), 2.93 (m, 1H), 1.61 (m, 4H), 1.02 (t, 6H, J=7.26 Hz).

2-(6-(2-Methyl-4-benzyloxyphenoxy)-3-pyridyl)-1-(morpholin-4-yl)ethane-1-thione

Yield: 84%.

¹H-NMR (CDCl₃); δ 8.02 (d, 1H, J=2.31 Hz), 7.78 (dd, 1H, J=2.31, 8.58 Hz), 7.46-7.33 (m, 5H), 6.98 (d, 1H, J=8.58 Hz), 6.89 (d, 1H, J=2.64 Hz), 6.83 (d, 2H, J=8.58 Hz), 5.04 (s, 2H), 4.36-4.31 (m, 4H), 4.23 (s, 2H), 3.73-3.65 (m, 2H), 3.52-3.48 (m, 2H), 2.12 (s, 3H).

2-(6-(3-Methyl-4-benzyloxyphenoxy)-3-pyridyl)-1-(morpholin-4-yl)ethane-1-thione

Yield: 80%.

¹H-NMR (CDCl₃); δ 8.03 (d, 1H, J=2.64 Hz), 7.77 (dd, 1H, J=2.64; 8.58 Hz), 7.46-7.27 (m, 5H), 6.95 (s, 1H), 6.89 (s, 2H), 6.85 (d, 1H, J=8.58 Hz), 5.07 (s, 2H), 4.34-4.31 (m, 4H), 4.23 (s, 2H), 3.68-3.65 (m, 2H), 3.53-3.49 (m, 2H), 2.28 (s, 3H).

Reference Example 19 Synthesis of 2-(6-(4-benzyloxyphenoxy)-3-pyridyl)acetic acid

 

1-Morpholin-4-yl)-2-(6-(4-benzyloxyphenoxy)-3-pyridyl)ethane-1-thione (28.9 g, 71 mmol) obtained by the Reference Example 17 was dissolved in a mixture (2:1, 300 ml) of ethanol-30% aqueous solution of sodium hydroxide and stirred for 1 hour in a bath of 100° C. After completing the reaction, the reaction product was acidified by the addition of 50% aqueous solution of citric acid (250 ml), extracted with methylene chloride (250×3), washed with water, dried with magnesium sulfate and concentrated to obtain the subject compound (22.8 g, 68.0 mmol). The result of ¹H-NMR was consistent with the above structure.

Yield: 96%.

¹H-NMR (CDCl₃); δ 9.90 (br, 1H), 8.08 (s, 1H), 7.61 (dd, 1H, J=2.64, 8.58 Hz), 7.45-7.31 (m, 5H), 7.06-6.96 (m, 4H), 6.80 (d, 1H, J=8.58 Hz), 5.04 (s, 2H), 3.56 (s, 2H).

Reference Example 20

The following compounds were synthesized by a method similar to the Reference Example 19 using corresponding substrates. The results of ¹H-NMR were consistent with the structures.

2-(6-(6-Benzyloxy-2-naphthyloxy)-3-pyridyl)acetic acid

Yield: 73%.

¹H-NMR (CDCl₃); δ 3.62 (s, 2H), 5.18 (s, 2H), 6.92 (d, 1H, J=8.25 Hz), 7.23-7.76 (m, 12H), 8.10 (s, 1H).

2-(6-(4-Benzyloxyphenylthio)-3-pyridyl)acetic acid

Yield: 38%.

¹H-NMR (DMSO-d₆); δ 12.44 (br, 1H), 8.01 (s, 1H), 7.74 (d, 1H, J=8.25 Hz), 7.38-7.21 (m, 7H), 7.05 (d, 2H, J=8.91 Hz), 6.97 (d, 1H, J=8.25 Hz), 4.22 (s, 2H), 3.58 (s, 2H).

2-(6-(4-(1-Ethylpropylthio)phenoxy)-3-pyridyl)acetic acid

Yield: 24% (two steps from the Reference Example 18).

¹H-NMR (CDCl₃); δ 10.34 (br, 1H), 8.12 (d, 1H, J=2.31 Hz), 7.66 (dd, 1H, J=2.31, 8.58 Hz), 7.42 (d, 2H, J=8.58 Hz), 7.04 (d, 2H, J=8.58 Hz), 6.86 (d, 1H, J=8.58 Hz), 3.60 (s, 2H), 2.93 (m, 1H), 1.61 (m, 4H), 1.01 (t, 6H, J=7.26 Hz).

2-(6-(2-Methyl-4-benzyloxyphenoxy)-3-pyridyl)acetic acid

Yield: 78%.

¹H-NMR (CDCl₃); δ 8.03 (dd, 1H, J=2.64, 17.49 Hz), 7.62 (d, 1H, J=8.25 Hz, 7.45-7.30 (m, 5H), 6.97 (d, 1H, J=8.58 Hz), 6.89 (d, 1H, J=2.64 Hz), 6.84-6.78 (m, 2H), 5.04 (s, 2H), 2.14 (s, 2H), 2.08 (s, 3H).

2-(6-(3-Methyl-4-benzyloxyphenoxy)-3-pyridyl)acetic acid

Yield: 55%.

¹H-NMR (CDCl₃); δ 8.08 (d, 1H, J=2.31 Hz), 7.62 (dd, 1H, J=2.31, 8.25 Hz), 7.46-7.30 (m, 5H), 6.94 (s, 1H), 6.90-6.89 (m, 2H), 6.83 (d, 1H, J=8.58 Hz), 5.07 (s, 2H), 3.60 (s, 2H), 2.28 (s, 3H).

Reference Example 21 Synthesis of 2-((4-(6-benzyloxy-2-naphthyloxy)phenyl)acetylamino)benzoic acid methyl ester

 

Oxalyl chloride (3.84 ml, 44.1 mmol) was dropped into a dry methylene chloride solution (200 ml) of 4-(6-benzyloxy-2-naphthoxy)phenylacetic acid (15.4 g, 4006 mmol) obtained by the Reference Example 5 in nitrogen atmosphere, 5 drops of DMF were added with a pipette and the mixture was stirred for 2.5 hours at 35° C. The reaction liquid was concentrated and the residue was dissolved in dry methylene chloride (200 ml). The obtained solution was dropped into a dry methylene chloride solution (200 ml) of methyl anthranylate (5.18 ml, 40.06 mmol) and triethylamine (6.14 ml, 44.1 mmol) under ice cooling in nitrogen atmosphere, and the mixture was stirred as it is for 1.5 hours and then for a night at room temperature. After completing the reaction, water is added to the reaction liquid, extracted twice with chloroform, washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography to obtain the subject compound (17.5 g, 33.8 mmol). The result of ¹H-NMR was consistent with the above structure. Colorless acicular crystal.

Yield: 84%.

¹H-NMR (CDCl₃); δ 3.75 (s, 2H), 3.88 (s, 3H), 5.17 (s, 2H), 7.02-7.11 (m, 3H), 7.20-7.26 (m, 3H), 7.32-7.56 (m, 9H), 7.62 (d, J=9.6 Hz, 1H), 7.70 (d, J=8.9 Hz, 1H), 8.01 (dd, J=1.7, 8.2 Hz, 1H), 8.73 (dd, J=1.0, 8.3 Hz, 1H), 11.08 (br.s, 1H).

Reference Example 22

The following compounds were synthesized by a method similar to the Reference Example 21 using corresponding substrates. The results of ¹H-NMR were consistent with the structures.

2-((4-(6-Benzyloxy-2-naphthyloxy)phenyl)carbonylamino)benzoic acid methyl ester

Yield: 93%.

¹H-NMR (CDCl₃); δ 3.95 (s, 3H), 5.20 (s, 2H), 7.00-7.15 (m, 2H), 7.20-7.30 (m, 4H), 7.35-7.45 (m, 4H), 7.49 (d, J=1.0 Hz, 2H), 7.50-7.60 (m, 1H), 7.60-7.70 (m, 1H), 7.76 (d, J=8.9 Hz, 1H), 8.04 (dd, J=2.0, 9.9 Hz, 2H), 8.10 (d, J=1.7 Hz, 1H), 8.90 (dd, J=1.0, 9.5 Hz, 1H), 12.0 (brs, 1H).

2-((4-(4-Benzyloxyphenoxy)phenyl)carbonylamino)benzoic acid methyl ester

Yield: 87%.

¹H-NMR (CDCl₃); δ 12.00 (m, 1H), 8.91 (m, 1H), 8.02 (m, 3H), 7.61 (m, 1H), 6.98-7.45 (m, 12H), 5.08 (s, 2H), 3.97 (s, 3H).

2-(2-(4-(4-Benzyloxyphenoxy)phenyl)acetylamino)benzoic acid methyl ester

Yield: 75%.

¹H-NMR (CDCl₃); δ 3.72 (2H, s), 3.87 (3H, s), 5.04 (2H, s), 6.91-7.02 (6H, m), 7.06 (1H, td, J=8.6, 1.6 Hz), 7.24-7.46 (7H, m), 7.52 (1H, td, J=8.0, 1.6 Hz), 7.99 (1H, dd, J=8.2, 1.6 Hz), 8.71 (1H, dd, J=8.6, 1.3 Hz), 11.03 (1H, brs).

Reference Example 23 Synthesis of 2-(2-(4-(6-hydroxy-2-naphthyloxy)phenyl)acetylamino)benzoic acid methyl ester

 

2-((4-(6-Benzyloxy-2-naphthyloxy)phenyl)acetylamino)benzoic acid methyl ester (15.0 g, 29.0 mmol) obtained by the Reference Example 21 was dissolved in chloroform (150 ml) under heating and Pd-black (1.57 g) was added to the solution. The reaction system was stirred for a night at room temperature in hydrogen atmosphere. The reaction liquid was filtered with celite and the filtrate was concentrated. The residue was recrystallized from acetonitrile to obtain the subject compound (10.5 g, 24.5 mmol). The result of ¹H-NMR was consistent with the above structure. Light brown granular crystal.

Yield: 92%.

¹H-NMR (CDCl₃); δ 3.76 (s, 2H), 3.89 (s, 3H), 5.26 (brs, 1H), 7.02-7.15 (m, 5H), 7.22 (dd, J=2.3, 8.9 Hz, 1H), 7.31-7.37 (m, 3H), 7.53 (dt, J=1.7, 8.9 Hz, 1H), 7.60 (d, J=9.2 Hz, 1H), 7.64 (d, J=8.9 Hz, 1H), 8.01 (dd, J=1.7, 8.3 Hz, 1H), 8.72 (d, J=8.3 Hz, 1H), 11.10 (brs, 1H).

Reference Example 24

The following compounds were synthesized by a method similar to the Reference Example 23 using corresponding substrates. The results of ¹H-NMR were consistent with the structures.

2-((4-(6-Hydroxy-2-naphthyloxy)phenyl)carbonylamino)benzoic acid methyl ester

Yield: 92%.

¹H-NMR (CDCl₃); δ 3.88 (s, 3H), 5.26 (brs, 1H), 6.90-7.20 (m, 6H), 7.35 (brs, 1H), 7.50-7.70 (m, 3H), 7.90-8.05 (m, 3H), 8.84 (d, J=7.6 Hz, 1H), 11.95 (brs, 1H).

2-((4-(4-Hydroxyphenoxy)phenyl)carbonylamino)benzoic acid methyl ester

Yield: 93%.

¹H-NMR (DMSO-d₆); δ 11.63 (brs, 1H), 9.57 (brs, 1H), 8.65 (d, 1H, J=8.25 Hz), 8.10 (dd, 1H, J=7.91, 1.32 Hz), 8.02 (d, 2H, J=8.58 Hz), 7.76 (dd, 1H, J=8.58, 7.26, 1.65 Hz), 7.32 (dd, 1H, J=7.92, 7.26, 0.99 Hz), 7.13 (d, 2H, J=8.91 Hz), 7.07 (d, 2H, J=8.91 Hz), 6.92 (d, 2H, J=8.91 Hz), 3.98 (s, 3H).

2-(2-(4-(4-Hydroxyphenoxy)phenyl)acetylamino)benzoic acid methyl ester

Yield: 66%.

¹H-NMR (DMSO-d₆); δ 3.70 (2H, s), 3.78 (3H, s), 6.76 (2H, d, J=8.9 Hz), 6.88 (4H, d-like, J=8.6 Hz), 7.18 (1H, t, J=7.5 Hz), 7.30 (2H, d, J=8.6 Hz), 7.59 (1H, t, J=7.8 Hz), 7.89 (1H, dd, J=7.9, 1.7 Hz), 8.29 (1H, d, J=7.6 Hz), 9.31 (1H, s), 10.61 (1H, brs).

Example 1

The following compounds were synthesized by a method similar to the Reference Example 21 using corresponding substrates. The results of ¹H-NMR were consistent with the structures.

2-(2-(6-(4-Benzyloxyphenoxy)-3-pyridyl)acetylamino)benzoic acid methyl ester (Compound No. 1078)

Yield: 36%.

¹H-NMR (CDCl₃); δ 11.16 (brs, 1H), 8.68 (dd, 1H, J=0.66, 8.58 Hz), 8.16 (d, 1H, J=2.31 Hz), 7.99 (dd, 1H, J=1.65, 8.24 Hz), 7.70 (dd, 1H, J=2.31, 8.57 Hz), 7.53-729 (m, 6H), 7.09-6.96 (m, 6H), 6.87 (d, 1H, J=8.58 Hz), 5.03 (s, 2H), 3.86 (s, 3H), 3.68 (s, 2H).

2-(2-(6-(6-Benzyloxy-2-naphthyloxy)-3-pyridyl)acetylamino)benzoic acid methyl ester (Compound No. 1120)

Yield: 58%.

¹H-NMR (CDCl₃); δ 3.72 (s, 2H), 3.91 (s, 3H), 5.18 (s, 2H), 6.96 (d, 1H, J=8.58 Hz), 7.06-7.77 (m, 14H), 8.02 (dd, 1H, J=1.65, 8.08 Hz), 8.18 (d, 1H, J=2.47 Hz), 8.70 (d, 1H, J=7.42 Hz), 11.19 (br, 1H).

2-(2-(6-(4-(1-Ethylpropylthio)phenoxy)-3-pyridyl)acetylamino)benzoic acid methyl ester (Compound No. 1093)

Yield: 69%.

¹H-NMR (CDCl₃); δ 11.18 (brs, 1H), 8.69 (d, 1H, J=8.58 Hz), 8.19 (d, 1H, J=2.31 Hz), 8.01 (dd, 1H, J=1.65, 8.25 Hz), 7.75 (dd, 1H, J=2.64, 8.25 Hz), 7.53 (ddd, 1H, J=1.65, 7.26, 8.58 Hz), 7.42 (d, 2H, J=8.58 Hz), 7.07 (m, 3H), 6.93 (d, 1H, J=8.57 Hz), 3.89 (s, 3H), 3.72 (s, 2H), 2.91 (m, 1H), 1.60 (m, 4H), 1.01 (t, 6H, J=7.25 Hz).

2-(2-(6-(2-Methyl-4-benzyloxyphenoxy)-3-pyridyl)acetylamino)benzoic acid methyl ester (Compound No. 1094)

Yield: 21%.

¹H-NMR (CDCl₃); δ 11.15 (brs, 1H), 8.69 (d, 1H, J=8.58 Hz), 8.14 (s, 1H), 7.98 (d, 1H, J=7.91 Hz), 7.69 (dd, 1H, J=2.31, 8.58 Hz), 7.51 (dd, 1H, J=7.58, 8.25 Hz), 7.44-7.31 (m, 5H), 7.06 (dd, 1H, J=7.58, 7.91 Hz), 6.98 (d, 1H, J=8.58 Hz), 6.88-6.79 (m, 3H), 5.03 (s, 2H), 3.86 (s, 3H), 3.68 (s, 21), 2.16 (s, 3H).

2-(2-(6-(3-Methyl-4-benzyloxyphenoxy)-3-pyridyl)acetylamino)benzoic acid methyl ester (Compound No. 1095)

Yield: 62%.

¹H-NMR (CDCl₃); δ 11.18 (brs, 1H), 8.68 (d, 1H, J=8.24 Hz), 8.17 (d, 1H, J=2.31 Hz), 8.01 (dd, 1H, J=1.65, 8.24 Hz), 7.71 (dd, 1H, J=2.31, 8.24 Hz), 7.53 (ddd, 1H, J=1.65, 7.26, 8.90 Hz), 7.46-7.30 (m, 5H), 7.08 (ddd, 1H, J=0.99, 7.26, 8.24 Hz), 6.97-6.86 (m, 4H), 5.07 (s, 2H), 3.89 (s, 3H), 3.69 (s, 2H), 2.28 (s, 3H).

2-(2-(6-(4-Benzyloxyphenylthio)-3-pyridyl)acetylamino)benzoic acid methyl ester (Compound No. 1096)

Yield: 81%.

¹H-NMR (CDCl₃); δ 11.17 (brs, 1H), 8.68 (d, 1H, J=8.58 Hz), 8.18 (d, 1H, J=2.31 Hz), 8.00 (dd, 1H, J=1.32, 7.92 Hz), 7.74 (dd, 1H, J=2.31, 8.58 Hz), 7.52 (ddd, 1H, J=1.32, 7.26, 8.58 Hz), 7.33-7.20 (m, 7H), 7.11-7.03 (m, 3H), 6.91 (d, 1H, J=8.25 Hz), 4.08 (s, 2H), 3.88 (s, 3H), 3.71 (s, 2H).

2-((6-(4-Benzyloxyphenoxy)-3-pyridyl)carbonylamino)benzoic acid methyl ester (Compound No. 1100)

Yield: 65%.

¹H-NMR (CDCl₃); δ 12.08 (brs, 1H), 8.89 (s, 1H), 8.88 (d, 1H, J=6.6 Hz), 8.33 (dd, 1H, J=2.31, 8.58 Hz), 8.08 (dd, 1H, J=1.65, 7.92 Hz), 7.60 (t, 1H, J=7.26 Hz), 7.47-7.31 (m, 6H), 7.16-6.99 (m, 5H), 5.08 (s, 2H), 3.94 (s, 3H).

4-Nitro-2-(2-(6-(4-benzyloxyphenoxy)-3-pyridyl)acetylamino)benzoic acid methyl ester (Compound No. 1104)

Yield: 52% (in this case, coupled with 4-nitroanthranilic acid).

¹H-NMR (CDCl₃); δ 11.21 (brs, 1H), 9.60 (m, 1H), 8.17 (m, 2H), 7.88 (m, 1H), 7.71 (m, 1H), 7.43-7.25 (m, 5H), 7.10-6.89 (m, 5H), 5.06 (s, 2H), 3.96 (s, 3H), 3.74 (s, 2H).

5-Chloro-2-(2-(6-(4-benzyloxyphenoxy)-3-pyridyl)acetylamino)benzoic acid methyl ester (Compound No. 1110)

Yield: 72% (in this case, coupled with 5-chloroanthranilc acid).

¹H-NMR (CDCl₃); δ 11.05 (brs, 1H), 8.67 (d, 1H, J=8.91 Hz), 8.15 (d, 1H, J=2.64 Hz), 7.97 (d, 1H, J=2.64 Hz), 7.69 (dd, 1H, J=2.31, 8.57 Hz), 7.49-7.30 (m, 6H), 7.07 (d, 2H, J=8.90 Hz), 6.98 (d, 2H, J=9.24 Hz), 6.89 (d, 1H, 8.58 Hz), 5.05 (s, 2H), 3.89 (s, 3H), 3.69 (s, 2H).

3-Methyl-2-(2-(6-(4-benzyloxyphenoxy)-3-pyridyl)acetylamino)benzoic acid (Compound No. 1112)

Yield: 20% (in this case, coupled with 3-methylanthranilic acid).

¹H-NMR (DMSO-d₆); δ 11.94 (brs, 1H), 8.05 (s, 1H), 7.79 (d, 1H, J=8.58 Hz), 7.68 (d, 1H, J=7.25 Hz), 7.49-7.30 (m, 5H), 7.16 (d, 1H, J=7.59 Hz), 7.04 (s, 4H), 7.04 (m, 1H), 6.92 (d, 1H, J=8.24 Hz), 5.10 (s, 2H), 3.62 (s, 2H), 2.08 (s, 3H).

2-(2-(N-Methyl-6-(4-benzyloxyphenoxy)-3-pyridyl)acetylamino)benzoic acid methyl ester (Compound No. 1113)

Yield: 59%.

¹H-NMR (CDCl₃); δ 8.02 (dd, 1H, J=1.65, 7.92 Hz), 7.65-7.55 (m, 2H), 7.51-7.30 (m, 7H), 7.22 (d, 1H, J=7.58 Hz), 7.04 (d, 2H, J=9.24 Hz), 6.97 (d, 2H, J=9.24 Hz), 6.77 (d, 1H, J=8.24 Hz), 5.05 (s, 2H), 3.83 (s, 3H), 3.25 (s, 2H), 3.20 (s, 3H).

2-(2-(6-(6-Benzyloxy-2-naphthoxy)-3-pyridyl)acetylamino)benzoic acid methyl ester (Compound No. 1206)

Yield: 58%.

¹H-NMR (CDCl₃); δ 11.19 (br, 1H), 8.70 (d, 1H, J=7.42 Hz), 8.18 (d, 1H, J=2.47 Hz), 8.02 (dd, 1H, J=1.65, 8.08 Hz), 7.77-7.06 (m, 14H), 6.96 (d, 1H, J=8.58 Hz), 5.18 (s, 2H), 3.91 (s, 3H); 3.72 (s, 2H).

Example 2

The following compounds were synthesized by a method similar to the Reference Example 23 using corresponding substrates. The results of ¹H-NMR were consistent with the structures.

2-(2-(6-(4-Hydroxyphenoxy)-3-pyridyl)acetylamino)benzoic acid methyl ester (Compound No. 1076)

Yield: 78%.

¹H-NMR (DMSO-d₆); δ 10.63 (brs, 1H), 9.36 (brs, 1H), 8.20 (dd, 1H, J=0.99, 8.58 Hz), 8.08 (d, 1H, J=2.31 Hz), 7.89 (dd, 1H, J=1.32, 7.92 Hz), 7.78 (dd, 1H, J=2.31, 8.58 Hz), 7.59 (ddd, 1H, J=1.65, 6.93, 8.58 Hz), 7.19 (ddd, 1H, J=0.99, 6.93, 8.25 Hz), 6.94-6.89 (m, 3H), 6.77 (d, 2H, J=8.9 Hz), 3.79 (s, 3H), 3.74 (s, 2H).

2-(2-(6-(6-Hydroxy-2-naphthyloxy)-3-pyridyl)acetylamino)benzoic acid methyl ester (Compound No. 1204)

Yield: 82%.

¹H-NMR (CDCl₃); δ 3.72 (s, 2H), 3.91 (s, 3H), 5.18 (brs, 1H), 6.97 (d, 1H, J=8.25 Hz), 7.07-8.18 (m, 11H), 8.69 (d, 1H, J=7.92 Hz).

2-((6-(4-Hydroxyphenoxy)-3-pyridyl)carbonylamino)benzoic acid methyl ester (Compound No. 1099)

Yield: 73%.

¹H-NMR (DMSO-d₆); δ 11.41 (brs, 1H), 9.45 (brs, 1H), 8.69 (d, 1H, J=2.31 Hz), 8.41 (d, 1H, J=8.24 Hz), 8.29 (dd, 1H, J=2.64, 8.58 Hz), 7.98 (d, 1H, J=7.92 Hz), 7.67 (dd, 1H, J=7.25, 7.59 Hz), 7.25 (t, 1H, J=7.26 Hz), 7.11 (d, 1H, J=8.58 Hz), 7.00 (d, 2H, J=8.91 Hz), 6.80 (d, 2H, J=8.91 Hz), 3.86 (s, 3H).

Example 3 Synthesis of 2-(2-(6-(4-benzyloxyphenoxy)-3-pyridylacetylamino)benzoic acid (Compound No. 986)

 

2-(2-(6-(4-Benzyloxyphenoxy)-3-pyridyl)acetylamino)benzoic acid methyl ester (87 mg, 0.186 mmol) obtained by the Example 1 was dissolved in a 2:1 mixed solvent (6 ml) of THF and methanol, 4N-lithium hydroxide (1 ml) was added thereto and the mixture was stirred for 1 hour at room temperature. After completing the reaction, the pH of the product was adjusted to about 4 with 10% aqueous solution of citric acid and the reaction product was extracted with ethyl acetate, washed with water, dried with magnesium sulfate and concentrated, and the residue was recrystallized from acetonitrile (20 ml) to obtain the subject compound (66 mg, 0.145 mmol). The result of ¹H-NMR was consistent with the above structure.

Yield: 78%.

¹H-NMR (DMSO-d₆); δ 13.56 (br, 1H), 11.18 (brs, 1H), 8.47 (d, 1H, J=8.25 Hz), 8.09 (d, 1H, J=1.98 Hz), 7.96 (dd, 1H, J=1.65, 7.92 Hz), 7.80 (d, 1H, J=8.58 Hz), 7.57 (t, 1H, J=7.92 Hz), 7.48-7.31 (m, 5H), 7.14 (t, 1H, J=7.59 Hz), 7.05 (s, 4H), 6.95 (d, 1H, J=8.25 Hz), 5.11 (s, 2H), 3.76 (s, 2H).

Example 4

The following compounds were synthesized by a method similar to the Example 3 using corresponding substrates.

2-(2-(6-(4-(1-Ethylpropylthio)phenoxy)-3-pyridyl)acetylamino)benzoic acid (Compound No. 1027)

Yield: 75%.

¹H-NMR (DMSO-d₆); δ 13.55 (br, 1H), 11.18 (brs, 1H), 8.47 (d, 1H, J=8.25 Hz), 8.13 (s, 1H), 7.96 (d, 1H, J=7.91 Hz), 7.85 (d, 1H, J=8.58 Hz), 7.57 (t, 1H, J=7.92 Hz), 7.42 (d, 2H, J=8.58 Hz), 7.17-7.02 (m, 4H), 3.79 (s, 2H), 3.04 (m, 1H), 1.54 (m, 4H), 0.99 (t, 6H, J=7.26 Hz).

2-(2-(6-(2-Methyl-4-benzyloxyphenoxy)-3-pyridyl)acetylamino)benzoic acid (Compound No. 1039)

Yield: 83%.

¹H-NMR (DMSO-d₆); δ 11.26 (brs, 1H), 8.45 (d, 1H, J=8.58 Hz), 8.04 (s, 1H), 7.95 (d, 1H, J=7.92 Hz), 7.78 (d, 1H, J=8.58 Hz), 7.56 (dd, 1H, J=7.26, 8.57 Hz), 7.48-7.31 (m, 5H), 7.13 (dd, 1H, J=7.26, 7.92 Hz), 6.98-6.83 (m, 4H), 5.09 (s, 2H), 3.74 (s, 2H), 2.05 (s, 3H).

2-(2-(6-(3-Methyl-4-benzyloxyphenoxy)-3-pyridyl)acetylamino)benzoic acid (Compound No. 1040)

Yield: 59%.

¹H-NMR (DMSO-d₆); δ 13.70-13.40 (br, 1H), 11.24 (brs, 1H), 8.46 (d, 1H, J=8.25 Hz), 8.09 (d, 1H, J=2.31 Hz), 7.96 (d, 1H, J=7.92 Hz), 7.80 (dd, 1H, J=2.31, 8.25 Hz), 7.57 (dd, 1H, J=7.26, 8.58 Hz), 7.50-7.31 (m, 5H), 7.14 (dd, 1H, J=7.26, 7.92 Hz), 7.03 (d, 1H, J=8.58 Hz), 6.97-6.88 (m, 3H), 5.13 (s, 2H), 3.76 (s, 2H), 2.20 (s, 3H).

2-(2-(6-(4-Benzyloxyphenylthio)-3-pyridyl)acetylamino)benzoic acid (Compound No. 1053)

Yield: 91%.

¹H-NMR (DMSO-d₆); δ 13.57 (br, 1H), 11.16 (brs, 1H), 8.46 (d, 1H, J=8.25 Hz), 8.12 (d, 1H, J=1.98 Hz), 7.95 (d, 1H, J=7.92 Hz), 7.84 (dd, 1H, J=2.31, 8.24 Hz), 7.57 (dd, 1H, J=7.26, 8.25 Hz), 7.38-7.21 (m, 7H), 7.14 (dd, 1H, J=7.26, 7.91 Hz), 7.06 (d, 2H, J=8.57 Hz), 7.01 (d, 1H, J=8.25 Hz), 4.22 (s, 2H), 3.78 (s, 2H).

4-Nitro-2-(2-(6-(4-benzyloxyphenoxy)-3-pyridyl)acetylamino)benzoic acid (Compound No. 1071)

Yield: 85%.

¹H-NMR (DMSO-d₆); δ 11.28 (brs, 1H), 9.28 (s, 1H), 8.18 (d, 1H, J=8.91 Hz), 8.10 (s, 1H), 7.95 (d, 1H, J=8.91 Hz), 7.82 (d, 1H, J=8.58 Hz), 7.48-7.30 (m, 5H), 7.05 (s, 4H), 6.96 (d, 1H, J=8.58 Hz), 5.10 (s, 2H), 3.83 (s, 2H).

5-Chloro-2-(2-(6-(4-benzyloxyphenoxy)-3-pyridyl)acetylamino)benzoic acid (Compound No. 1111)

Yield: 72%.

¹H-NMR (DMSO-d₆); δ 11.08 (brs, 1H), 8.47 (d, 1H, J=8.91 Hz), 8.08 (d, 1H, J=2.31 Hz), 7.89 (d, 1H, J=2.64 Hz), 7.80 (dd, 1H, J=1.98, 8.25 Hz), 7.64 (dd, 1H, J=2.31, 8.91 Hz), 7.48-7.31 (m, 5H), 7.05 (s, 4H), 6.95 (d, 1H, J=8.53 Hz), 5.11 (s, 2H), 3.77 (s, 2H).

2-(2-(N-Methyl-6-(4-benzyloxyphenoxy)-3-pyridyl)acetylamino)benzoic acid (Compound No. 1114)

Yield: 54%.

¹H-NMR (DMSO-d₆); δ 10.35 (br, 1H), 8.07 (d, 1H, J=1.65 Hz), 8.05 (dd, 1H, J=1.32, 8.25 Hz), 7.78 (dd, 1H, J=2.31, 8.58 Hz), 7.66 (dd, 1H, J=7.58, 7.92 Hz), 7.54-7.26 (m, 7H), 7.11 (d, 2H, J=9.24 Hz), 7.09 (d, 2H, J=9.56 Hz), 7.00 (d, 1H, J=8.58 Hz), 5.12 (s, 2H), 3.61 (s, 3H), 3.32 (s, 2H).

2-(2-(6-(6-Benzyloxy-2-naphthoxy)-3-pyridyl)acetylamino)benzoic acid (Compound No. 1120)

Yield: 97%.

¹H-NMR (CDCl₃); δ 3.71 (s, 2H), 5.19 (s, 2H), 6.93 (d, 1H, J=8.41 Hz), 7.04-7.77 (m, 14H), 8.06 (dd, 1H, J=1.57, 8.00 Hz), 8.18 (d, 1H, J=2.31 Hz), 8.67 (d, 1H, J=9.24 Hz), 11.51 (br, 1H).

Example 5 Synthesis of 2-(2-(4-(6-(2-ethoxyethoxy)-2-naphthyloxy)phenyl)acetylamino)benzoic acid methyl ester (methyl ester of the Compound No. 1)

 

2-(2-(4-(6-Hydroxy-2-naphthyloxy)phenyl)acetylamino)benzoic acid methyl ester (214 mg, 0.50 mmol) obtained by the Reference Example 23 was dissolved in 5 ml of dry DMF under nitrogen atmosphere, potassium carbonate (104 mg, 0.75 mmol) was added to the solution and the mixture was stirred as it is for 1 hour. at room temperature. The reaction liquid was added with 2-ethoxyethyl bromide (84 mg, 0.55 mmol) and stirred for 3.5 hours at room temperature and for 4 hours at 80° C. The obtained reaction liquid was added with water and extracted twice with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride and dried with anhydrous sodium sulfate, and the solvent was distilled out under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1 to 5:1) to obtain the subject compound (199 mg, 0.398 mmol). The result of ¹H-NMR was consistent with the above structure. Colorless oil.

Yield: 80%.

¹H-NMR (CDCl₃); δ 1.27 (t, J=6.9 Hz, 3H), 3.64 (q, J=6.9 Hz, 2H), 3.75 (s, 2H), 3.84-3.88 (m, 2H), 3.88 (s, 3H), 4.24 (t, J=4.6 Hz, 2H), 7.02-7.25 (m, 6H), 7.31-7.37 (m, 3H), 7.50-7.57 (m, 1H), 7.60 (d, J=8.9 Hz, 1H), 7.69 (d, J=8.9 Hz, 1H), 8.01 (dd, J=1.7, 8.3 Hz, 1H), 8.73 (dd, J=1.0, 8.6 Hz, 1H), 11.07 (br.s, 1H).

Example 6

The compounds described as the Example No. 6 in the Tables 44 to 72 and the methyl ester of the Compound No. 88 were synthesized by a method similar to the Example 5 using corresponding substrates. The compounds were identified by ¹H-NMR and the data were consistent with the structures. These data are described in the Tables 44 to 72 and the Table 74. The Table 74 only describes the yield.

Example 7 Synthesis of 2-(2-(4-(6-(2-ethoxyethoxy)-2-naphthyloxy)phenyl)-acetylamino)benzoic acid (Compound No. 1)

 

2-(2-(4-(6-(2-Ethoxyethoxy)-2-naphthyloxy)phenyl)acetylamino)-benzoic acid methyl ester (187 mg, 0.37 mmol) obtained by the Example 5 was dissolved in a mixed solvent composed of methanol/THF (3 ml/6 ml), 4N aqueous solution of lithium hydroxide (0.94 ml, 3.7 mmol) was added to the solution and the mixture was stirred at room temperature for a night. After completing the reaction, 5N hydrochloric acid was added to adjust the pH of the system to about 1 and the system was stirred for 0.5 hour at room temperature. Water was added to the reaction liquid and the product was extracted twice with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride and dried with anhydrous sodium sulfate, and the solvent was distilled off. The residue was recrystallized from acetonitrile (1 ml) to obtain the subject compound (123 mg, 0.253 mmol). The result of ¹H-NMR was consistent with the structure. Colorless plate crystal.

Yield: 68%.

¹H-NMR (DMSO-d₆); δ 1.13 (t, J=6.9 Hz, 3H), 3.52 (q, J=6.9 Hz, 2H), 3.73-3.76 (m, 4H), 4.18 (t, J=4.3 Hz, 2H), 7.02 (d, J=8.6-Hz, 2H), 7.10-7.18 (m, 2H), 7.22-7.26 (m, 1H), 7.34-7.39 (m, 4H), 7.57 (t, J=8.9 Hz, 1H), 7.73 (d, J=8.9 Hz, 1H), 7.83 (d, J=8.9 Hz, 1H), 7.95 (dd, J=1.7, 7.9 Hz, 1H), 8.50.(d, J=8.3 Hz, 1H), 11.12 (brs, 1H), 13.57 (brs, 1H).

Example 8

The compounds described as the Example No. 8 in the Tables 44 to 72 and the compounds shown in the Table 74 were synthesized by a method similar to the Example 7 using corresponding substrates. The compounds were identified by ¹H-NMR or LC-MS and the results were consistent with the above structures. These data are described in the Tables 44 to 72 and the Table 74.

Example 9 Synthesis of 2-(2-(4-(4-((2-furanyl)methoxy)phenoxy)phenyl)acetylamino)-benzoic acid methyl ester (methyl ester of the Compound No. 428)

 

Triphenylphosphine (216 mg, 0.83 mmol), 2-furanylmethanol (81 mg, 0.83 mmol) and 40% toluene solution of diethyl azodicarboxylate (360 mg, 0.83 mmol) were added to 2-(2-(4-(4-hydroxyphenoxy)phenyl)-acetylamino)benzoic acid methyl ester (100 mg, 0.28 mmol) obtained by the Reference Example 24 in nitrogen atmosphere and stirred for 2 hours at room temperature. After completing the reaction, the reaction liquid was concentrated and the obtained crude product was purified by silica gel column chromatography to obtain the subject compound (73 mg, 0.16 mmol). The result of

¹H-NMR was consistent with the above structure.

Yield: 57%.

¹H-NMR (CDCl₃); δ 3.73 (2H, s), 3.87 (3H, s), 4.98 (2H, s), 6.37-6.43 (2H, m), 6.87-7.01 (6H, m), 7.07 (1H, t, J=7.0 Hz), 7.31 (2H, d, J=8.6 Hz), 7.45-7.56 (2H, m), 7.99 (1H, dd, J=7.9, 1.7 Hz), 8.71 (1H, d, J=8.3 Hz), 11.03 (1H, brs).

Example 10

The compounds described as the Example No. 10 in the Tables 44 to 72 and the methyl esters of the compounds described in the Table 73 were synthesized by a method similar to the Example 9 using corresponding substrates. The compounds were identified by ¹H-NMR and the results were consistent with the above structures. These data are shown in the Tables 44 to 72 and the Table 74. The Table 73 only describes the yield.

Example 11

The compounds described as the Example No. 11 in the Tables 44 to 72 and the compounds described in the Table 73 were synthesized by a method similar to the Example 7 using corresponding substrates obtained by the Examples 2, 9 and 10. The compounds were identified by ¹H-NMR or LC-MS and the results were consistent with the above structures. These data are shown in the Tables 44 to 72 and the Table 73.

Example 12 Synthesis of 2-(2-(6-(4-benzyloxyphenylsulfinyl)-3-pyridyl)acetylamino)-benzoic acid methyl ester (Compound No. 1097)

 

2-(2-(6-(4-Benzyloxyphenylthio)-3-pyridyl)acetylamino)benzoic acid methyl ester (62 mg, 0.128 mmol) obtained by the Example 1 was dissolved in a mixed solvent (5 ml) composed of methanol and methylene chloride (3:2) and the solution was cooled with ice. The solution was added with N-bromosuccinimde (45 mg, 0.256 mmol) and stirred for 1.5 hours under ice cooling. After completing the reaction, the reaction liquid was concentrated and purified by silica gel chromatography to obtain the subject compound (36 mg, 0.0719 mmol) as the objective product. The compound was identified by ¹H-NMR and the result was consistent with the above structure.

Yield: 56%.

¹H-NMR (CDCl₃); δ 11.21 (brs, 1H), 8.69 (d, 1H, J=8.25 Hz), 8.20 (d, 1H, J=2.31 Hz), 8.02 (dd, 1H, J=1.32, 8.25 Hz), 7.79 (dd, 1H, J=2.31, 8.58 Hz), 7.54 (ddd, 1H, J=1.32, 7.25, 8.58 Hz), 7.39 (d, 2H, J=8.90 Hz), 7.30-7.20 (m, 5H), 7.12-7.02 (m, 3H), 6.97 (d, 1H, J=8.92 Hz), 4.11 (d, 1H, J=15.22 Hz), 3.99 (d, 1H, J=12.54 Hz), 3.89 (s, 3H), 3.74 (s, 2H).

Example 13 Synthesis of 2-(2-(6-(4-benzyloxyphenylsulfinyl)-3-pyridyl)acetylamino)-benzoic acid (Compound No. 1054)

 

2-(2-(6-(4-Benzyloxyphenylsulfinyl)-3-pyridyl)acetylamino)benzoic acid methyl ester (51 mg, 0.102 mmol) obtained by the Example 12 was dissolved in a mixed solvent (6 ml) composed of THF and methanol (2:1), added with 4N lithium hydroxide (1 ml) and stirred for 1 hour at room temperature. After completing the reaction, the pH of the reaction liquid was adjusted to about 7 using 1N aqueous solution of hydrochloric acid and a phosphate buffer solution, and the liquid was extracted with ethyl acetate, washed with water, dried with magnesium sulfate and concentrated. The residue was dissolved in a mixture of ethyl acetate and methanol (1:1) and hexane was added to the solution to precipitate a solid component and obtain the subject compound (35 mg, 0.0179 mmol) as the objective product. The compound was identified by ¹H-NMR and the result was consistent with the above structure.

Yield: 70%.

¹H-NMR (DMSO-d₆); δ 13.58 (br, 1H), 11.19 (brs, 1H), 8.47 (d, 1H, J=8.25 Hz), 8.18 (d, 1H, J=1.65 Hz), 7.96 (d, 1H, J=7.92 Hz), 7.90 (dd, 1H, J=2.31, 8.58 Hz), 7.57 (m, 3H), 7.25 (s, 5H), 7.17-7.07 (m, 4H), 4.27 (d, 1H, J=12.87 Hz), 4.10 (d, 1H, J=12.54 Hz), 3.81 (s, 2H).

Example 14 Synthesis of 2-(2-(1-hydroxy-6-(4-(1-ethylpropoxy)phenoxy)-3-pyridyl)acetylamino)benzoic acid (Compound No. 1246)

 

2-(2-(6-(4-(1-Ethylpropoxy)phenoxy)-3-pyridyl)acetylamino)benzoic acid (1.0 g, 2.30 mmol) obtained by the Example 11 was dissolved in a mixed solvent consisting of methylene chloride (30 ml) and methanol (10 ml) and m-chloroperbenzoic acid (50-60%, 0.99 g) was added to the solution in an ice bath. The reaction was continued as it is for 2 days, m-chloroperbenzoic acid (50-60%, 0.99 g) was added to the product in an ice bath and the reaction was continued for 2.5 hours. After completing the reaction, the system was added with excessive amount of saturated aqueous solution of sodium thiosulfate and stirred, the solvent was concentrated and the reaction product was extracted from the residue with methylene chloride. The organic solvent was washed with saturated aqueous solution of magnesium thiosulfate and water in the order, dried with anhydrous magnesium sulfate and concentrated. A small amount of ethyl acetate was added to the obtained residue to effect the dissolution of the residue, and hexane was added to the solution to precipitate a solid component and obtain the subject compound (0.18 g, 0.40 mmol) as the objective product. The compound was identified by ¹H-NMR and the result was consistent with the above structure.

Yield: 17%.

¹H-NMR (DMSO-d₆); δ 14.80-13.50 (br, 1H), 11.18 (brs, 1H), 8.45 (d, 1H, J=8.58 Hz), 8.39 (d, 1H, J=1.98 Hz), 7.97 (dd, 1H, J=1.65, 7.92 Hz), 7.58 (ddd, 1H, J=1.65, 7.26, 8.58 Hz), 7.33 (dd, 1H, J=1.98, 8.58 Hz), 7.16 (dd, 1H, J=7.26, 7.92 Hz), 7.10 (d, 1H, J=8.58 Hz), 6.96 (s, 4H), 4.16 (qui, 1H, J=5.94 Hz), 3.81 (s, 2H), 1.60 (dq, 4H, J=5.94, 7.59 Hz), 0.90 (t, 6H, J=7.59 Hz).

Example 15 Synthesis of 2-(2-(4-(4-(cis-4-(N,N-dibenzylamino)cyclohexyloxy)phenoxy)-phenyl)acetyl amino)benzoic acid methyl ester

 

2-(2-(4-(4-Hydroxyphenoxy)phenyl)acetylamino)benzoic acid methyl ester (5.66 g, 15.0 mmol) obtained by the Reference Example 24 was dissolved together with trans-4-(N,N-dibenzylamino)cyclohexanol (8.73 g, 29.6 mmol) and PPh₃ (7.87 g, 30.0 mmol) in N-methylmorpholine (90 ml) and cooled with ice. Azodicarboxylic acid diethyl ester (13.1 ml, 40% in PhMe, 30.0 mmol) was dropped into the solution spending 10 minutes. The mixture was stirred for a night at room temperature and the reaction liquid was concentrated. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=20:1 to 7:1) to obtain the subject compound (7.03 g, 10.7 mmol). The ¹H-NMR of the product was consistent with the above structure. Colorless foam.

Yield: 72%.

¹H-NMR (CDCl₃); δ 1.3-1.5 (m, 2H), 1.6-1.8 (m, 2H), 1.8-1.9 (m, 2H), 2.0-2.2 (m, 2H), 2.5-2.7 (m, 1H), 3.68 (s, 4H), 3.72 (s, 2H), 3.87 (s, 3H), 4.39 (br, 1H), 6.86 (d, J=9.1 Hz, 2H), 6.95-6.98 (m, 4H), 7.06 (t, J=7.3 Hz, 1H), 7.17-7.23 (m, 2H), 7.26-7.32 (m, 6H), 7.37-7.40 (m, 4H), 7.52 (t, J=7.3 Hz, 1H), 7.99 (dd, J=1.8, 8.1 Hz, 1H), 8.72 (d, J=8.7 Hz, 1H), 11.03 (brs, 1H).

Example 16

The following compounds were synthesized by a method similar to the Example 15 using corresponding substrates. The results of ¹H-NMR were consistent with the structures of respective compounds.

2-(2-(4-(6-(cis-4-(N,N-Dibenzylamino)cyclohexyloxy)-2-naphthyloxy)-phenyl)acetylamino)benzoic acid methyl ester

Yield: 81%.

¹H-NMR (CDCl₃); δ 11.07 (brs, 1H), 8.72 (d, 1H, J=7.56 Hz), 8.00 (dd, 1H, J=8.10, 1.35 Hz), 7.68-7.49 (m, 2H), 7.40-7.02 (m, 20H), 4.59 (br, 11H), 3.88 (s, 3H), 3.74 (s, 2H), 3.69 (s, 4H), 2.61 (m, 1H), 2.21-2.16 (m, 2H), 2.04-1.69 (m, 4H), 1.50-1.42 (m, 2H).

2-((4-(6-(cis-4-(N,N-Dibenzylamino)cyclohexyloxy)-2-naphthyloxy)phenyl)-carbonylamino)benzoic acid methyl ester

Yield: 64%.

¹H-NMR (CDCl₃); δ 12.00 (s, 1H), 8.92 (d, 1H, J=8.58 Hz), 8.06 (m, 2H), 7.66 (m, 2H), 7.09-7.41 (m, 19H), 4.62 (s, 1H), 3.95 (s, 3H), 3.71 (s, 4H), 2.62 (m, 1H), 2.21 (m, 2H), 1.89 (m, 2H), 1.73 (m, 2H), 1.45 (m, 2H).

2-(2-(4-(7-(cis-4-(N,N-Dibenzylamino)cyclohexyloxy)-2-naphthyloxy)-phenyl)acetylamino)benzoic acid methyl ester

Yield: 71%.

¹H-NMR (CDCl₃); δ 11.10 (brs, 1H), 8.74 (d, 1H, J=8.25 Hz), 7.99 (dd, 1H, J=7.91, 1.32 Hz), 7.72-7.67 (m, 3H), 7.52 (dd, 1H, J=8.58, 7.25 Hz), 7.49-6.98 (m, 18H), 4.56 (br, 1H), 3.88 (s, 3H), 3.75 (s, 2H), 3.68 (s, 4H), 2.59 (m, 1H), 2.04 (m, 2H), 1.88-1.68 (m, 4H), 1.43 (m, 2H).

2-((4-(4-(cis-4-(N,N-Dibenzylamino)cyclohexyloxy)phenoxy)phenyl)-carbonyl amino)benzoic acid methyl ester

Yield: 93%.

¹H-NMR (CDCl₃); δ 11.97 (brs, 1H), 8.91 (d, 1H, J=8.58 Hz), 8.07 (dd, 1H, J=7.75, 1.32 Hz), 8.00 (d, 2H, J=8.91 Hz), 7.59 (ddd, 1H, J=8.58, 7.09, 1.65 Hz), 7.40-6.90 (m, 17H), 4.43 (br, 1H), 3.95 (s, 3H), 3.69 (s, 4H), 2.60 (m, 1H), 2.11-1.23 (m, 8H).

2-(2-(4-(4-(1-Benzylpiperidin-2-ylmethyloxy)phenyloxy)phenyl)-acetylamino)benzoic acid methyl ester

Yield: 27%.

¹H-NMR (CDCl₃); δ 11.03 (s, 1H), 8.71 (dd, 1H, J=8.4, 1.1 Hz), 7.98 (dd, 1H, J=8.1, 1.6 Hz), 7.52 (ddd, 1H, J=8.4, 7.3, 1.6 Hz), 7.23-7.37 (m, 7H), 7.06 (ddd, 1H, J=8.1, 7.3, 1.1 Hz), 6.92 (d, 2H, J=8.9 Hz), 6.82 (d, 2H, J=8.9 Hz), 6.55 (d, 2H, J=8.9 Hz), 3.86 (s, 3H), 3.72 (d, 1H, J=13.5 Hz), 3.72 (s, 2H), 3.59 (d, 1H, J=13.5 Hz), 2.89-2.99 (brm, 1H), 2.76-2.88 (brm, 1H), 2.60-2.68 (m, 2H), 2.04-2.13 (br, 1H), 1.67-1.78 (brm, 6H).

2-(2-(4-(4-(1-Benzylpiperidin-3-ylmethyloxy)phenyloxyl)phenyl)-acetylamino)benzoic acid methyl ester

Yield: 60%.

¹H-NMR (CDCl₃); δ 11.03 (s, 1H), 8.71 (d, 1H, J=8.4 Hz), 7.99 (dd, 1H, J=8.1 Hz, 1.6 Hz), 7.52 (ddd, 1H, J=8.4 Hz, 7.3 Hz, 1.6 Hz), 7.24-7.32 (m, 7H), 7.06 (dd, 1H, J=8.1 Hz, 7.3 Hz), 6.93-6.98 (m, 4H), 6.82 (d, 2H, J=8.9 Hz), 3.87 (s, 3H), 3.72 (s, 2H), 3.56 (d, 1H, J=13.2 Hz), 3.48 (d, 1H, J=13.2 Hz), 2.14 (brm, 2H), 1.95-2.02 (m, 2H), 1.75-1.89 (m, 1H), 1.66-1.69 (brm, 6H).

2-(2-(4-(4-(2-Dibenzylaminocyclohexyloxy)phenyloxy)phenyl)acetylamino)-benzoic acid methyl ester

Yield: 13%.

¹H-NMR (CDCl₃); δ 11.05 (s, 1H), 8.72 (d, 1H, J=8.6 Hz), 8.00 (dd, 1H, J=8.1 Hz, 1.6 Hz), 7.52 (ddd, 1H, J=8.6 Hz, 7.0 Hz, 1.6 Hz), 7.15-7.38 (m, 12H), 7.06 (dd, 1H, J=8.1 Hz, 7.0 Hz), 6.91-7.02 (m, 6H), 4.26 (brm, 1H), 3.87 (s, 3H), 3.81 (s, 2H), 3.73 (s, 2H), 3.69 (s, 2H), 2.83 (brm, 1H), 2.16 (br, 1H), 2.00 (br, 1H), 1.70 (brm, 2H), 1.61 (brs, 1H), 1.30-1.50 (brm, 1H), 1.18-1.26 (m, 2H).

Example 17 Synthesis of 2-(2-(4-(4-(cis-4-aminocyclohexyloxy)phenoxy)phenyl)-acetylamino)benzoic acid methyl ester

 

2-(2-(4-(4-cis-4-(N,N-Dibenzylamino)cyclohexyloxyphenoxy)phenyl)-acetylamino)benzoic acid methyl ester (7.03 g, 10.74 mmol) obtained by the Example 15 was dissolved in a mixed solvent consisting of methanol (60 ml) and methylene chloride (60 ml), formic acid (5.3 ml, 0.14 mol) and Pd-Black (3.6 g) were added to the solution and the obtained mixture was stirred for 8 hours at room temperature. The reaction liquid was filtered with Celite and the filtrate was concentrated. The residue was dissolved in ethyl acetate and adjusted to pH>13 by the addition of concentrated ammonia water. The solution was extracted twice with ethyl acetate, and the organic layer was washed with saturated saline water, dried with anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→simple ethyl acetate→chloroform:methanol:triethylamine=100:10:1) to obtain the subject compound (4.60 g, 9.69 mmol). The ¹H-NMR of the product was consistent with the above structure. Pale yellow viscous liquid.

Yield: 90%.

¹H-NMR (CDCl₃); δ 1.35 br, 2H), 1.5-1.7 (m, 6H), 1.95-2.15 (m, 2H), 2.78 (br, 1H), 3.72 (s, 2H), 3.88 (s, 3H), 4.39 (br, 1H), 6.85-6.89 (m, 2H), 6.95-6.98 (m, 4H), 7.06 (t, J=7.4 Hz, 1H), 7.31 (d, J=8.2 Hz, 2H), 7.52 (t, J=7.3 Hz, 1H), 7.99 (dd, J=1.7, 8.1 Hz, 1H), 8.71 (d, J=8.7 Hz, 1H), 11.03 (brs, 1H).

Example 18

The following compounds were synthesized by a method similar to the Example 17 using corresponding substrates. The results of ¹H-NMR were consistent with the structures of respective compounds.

2-((4-(4-(cis-4-Aminocyclohexyloxy)phenoxy)phenyl)carbonylamino)benzoic acid methyl ester

Yield: 57%.

¹H-NMR (CDCl₃); δ 11.98 (brs, 1H), 8.91 (d, 1H, J=8.37 Hz), 8.07 (d, 1H, J=7.83 Hz), 8.00 (d, 2H, J=8.64 Hz), 7.59 (dd, 1H, J=8.37, 7.56 Hz), 7.10 (dd, 1H, J=7.56, 7.29 Hz), 7.05-6.91 (m, 6H), 4.43 (br, 1H), 3.95 (s, 3H), 2.80 (br, 1H), 2.00 (m, 2H), 1.80-1.63 (m, 4H), 1.32 (m, 2H).

2-(2-(4-(6-(cis-4-Aminocyclohexyloxy)-2-naphthyloxy)phenyl)acetylamino)-benzoic acid methyl ester (methyl ester of the Compound No. 18)

Yield: 66%.

¹H-NMR (CDCl₃); δ 11.07 (brs, 1H), 8.72 (d, 1H, J=8.41 Hz), 8.00 (dd, 1H, J=8.08, 1.65 Hz), 7.68-7.49 (m, 3H), 7.36-7.02 (m, 9H), 4.58 (br, 1H), 3.88 (s, 3H), 3.74 (s, 2H), 2.80 (m, 1H), 2.09-2.04 (m, 2H), 1.70-1.46 (m, 6H).

2-((4-(6-(cis-4-Aminocyclohexyloxy)-2-naphthyloxy)phenyl)carbonylamino)benzoic acid methyl ester

Yield: 99%.

¹H-NMR (CDCl₃); δ 12.00 (s, 1H), 8.92 (d, 1H, J=8.58 Hz), 8.09 (m, 3H), 7.66 (m, 3H), 7.42 (s, 1H), 7.09-7.25 (m, 6H), 4.62 (s, 1H), 3.95 (s, 3H), 2.83 (m, 1H), 2.11 (m, 2H), 1.67 (m, 4H), 1.50 (br, 2H).

2-(2-(4-(7-(cis-4-Aminocyclohexyloxy)-2-naphthyloxy)phenylacetylamino)-benzoic acid methyl ester (methyl ester of the Compound No. 19)

Yield: 44%.

¹H-NMR (CDCl₃); δ 11.10 (brs, 1H), 8.72 (d, 1H, J=8.58 Hz), 7.99 (dd, 1H, J=7.91, 1.65 Hz), 7.68-7.63 (m, 2H), 7.52 (dd, 1H, J=7.26, 6.92 Hz), 7.36 (d, 2H, J=8.58 Hz), 7.16-6.97 (m, 7H), 4.60 (br, 1H), 3.87 (s, 3H), 3.75 (s, 2H), 3.27 (m, 1H), 2.21-2.16 (m, 2H), 2.02 (m, 4H), 1.61 (m, 2H).

(R)-2-(2-(4-(4-(Pyrrolidin-2-ylmethyloxy)phenyloxy)phenyl)acetylamino)-benzoic acid methyl ester

Yield: 32% (yield of two steps from the reaction similar to the Example 15)

¹H-NMR (CDCl₃); δ 11.04 (s, 1H), 8.71 (dd, 1H, J=8.6, 1.1 Hz), 7.99 (dd, 1H, J=8.1, 1.6 Hz), 7.52 (ddd, 1H, J=8.6, 7.3, 1.6 Hz), 7.30 (d, 2H, J=8.6 Hz), 7.06 (ddd, 1H, J=8.1, 7.3, 1.1 Hz), 6.85-6.99 (m, 6H), 4.11-4.18 (m, 1H), 4.04 (d, 1H, J=5.7 Hz), 3.88 (s, 3H), 3.72 (s, 2H), 3.09-3.41 (br, 1H), 3.12-3.19 (m, 2H), 2.89-2.94 (m, 1H), 1.75-2.08 (m, 4H).

2-(2-(4-(4-(1-Aminocyclopentan-1-ylmethyloxy)phenyloxy)phenyl)-acetylamino)benzoic acid methyl ester

Yield: 39% (yield of two steps from the reaction similar to the Example 15)

¹H-NMR (CDCl₃); δ 11.04 (s, 1H), 8.71 (d, 1H, J=8.4 Hz), 7.98 (dd, 1H, J=8.1 Hz, 1.6 Hz), 7.51 (ddd, 1H, J=8.4 Hz, 7.3 Hz, 1.6 Hz), 7.32 (d, 2H, J=8.6 Hz), 7.06 (dd, 1H, J=8.1 Hz, 7.3 Hz), 6.97 (d, 2H, J=8.6 Hz), 6.93 (s, 4H), 3.98-4.16 (br, 4H), 3.87 (s, 3H), 3.73 (s, 2H), 3.12 (s, 1H), 1.97-2.08 (brm, 2H), 1.63-1.73 (m, 6H).

(S)-2-(2-(4-(4-(Pyrrolidin-2-ylmethyloxy)phenyloxy)phenyl)acetylamino)-benzoic acid methyl ester

Yield: 32% (yield of two steps from the reaction similar to the Example 15)

¹H-NMR (CDCl₃); δ 11.04 (s, 1H), 8.71 (dd, 1H, J=8.6, 1.1 Hz), 7.99 (dd, 1H, J=8.1, 1.6 Hz), 7.52 (ddd, 1H, J=8.6, 7.3, 1.6 Hz), 7.30 (d, 2H, J=8.6 Hz), 7.06 (ddd, 1H, J=8.1, 7.3, 1.1 Hz), 6.85-6.99 (m, 6H), 4.65-5.55 (br, 1H), 4.11-4.18 (m, 1H), 4.04 (d, 1H, J=5.7 Hz), 3.88 (s, 3H), 3.72 (s, 2H), 3.12-3.19 (m, 2H), 2.89-2.94 (m, 1H), 1.75-2.08 (m, 4H).

2-(2-(4-(4-(Piperidin-2-ylmethyloxy)phenyloxy)phenyl)acetylamino)benzoic acid methyl ester

Yield: 37%.

¹H-NMR (CDCl₃); δ 11.04 (s, 1H), 8.71 (d, 1H, J=8.4 Hz), 7.99 (dd, 1H, J=8.1, 1.6 Hz), 7.51 (ddd, 1H, J=8.4, 7.3, 1.6 Hz), 7.31 (d, 2H, J=8.4 Hz), 7.06 (dd, 1H, J=8.1, 7.3 Hz), 6.91-6.97 (m, 6H), 5.20-5.75 (br, 1H), 3.87 (s, 3H), 3.72 (s, 2H), 3.35-3.42 (m, 2H), 3.23-3.33 (m, 2H), 1.69-2.04 (brm, 7H).

2-(2-(4-(4-(Piperidin-3-ylmethyloxy)phenyloxy)phenyl)acetylamino)benzoic acid methyl ester

Yield: 79%.

¹H-NMR (CDCl₃); δ 11.04 (s, 1H), 8.71 (dd, 1H, J=8.4, 1.1 Hz), 7.99 (dd, 1H, J=7.8, 1.6 Hz), 7.52 (ddd, 1H, J=8.4, 7.3, 1.6 Hz), 7.30 (d, 2H, J=8.9 Hz), 7.06 (ddd, 1H, J=7.8, 7.3, 1.1 Hz), 6.97 (d, 2H, J=8.9 Hz), 6.95 (d, 2H, J=8.9 Hz), 6.83 (d, 2H, J=8.9 Hz), 3.88 (s, 3H), 3.72 (s, 2H), 3.86-3.75 (m, 2H), 3.38-3.41 (brm, 1H), 3.21-3.26 (brm, 1H), 2.61-2.76 (brm, 2H), 2.16-2.28 (br, 2H), 1.90-1.97 (brm, 1H), 1.82 (br, 2H).

2-(2-(4-(4-(2-Aminocyclohexyloxy)phenyloxy)phenyl)acetylamino)benzoic acid methyl ester

Yield: 58%.

¹H-NMR (CDCl₃); δ 11.04 (s, 1H), 8.70 (dd, 1H, J=8.6, 1.1 Hz), 7.98 (dd, 1H, J=8.1, 1.6 Hz), 7.51 (ddd, 1H, J=8.6, 7.0, 1.6 Hz), 7.30 (d, 2H, J=8.6 Hz), 7.05 (ddd, 1H, J=8.1, 7.0, 1.1 Hz), 6.90-6.99 (m, 6H), 6.72 (br, 2H), 4.18 (brm, 1H), 3.86 (s, 3H), 3.71 (m, 2H), 2.95-3.01 (m, 1H), 2.17 (brm, 1H), 2.08 (brm, 1H), 1.71 (brm, 1H), 1.65 (brm, 1H), 1.33-1.43 (m, 2H), 1.21-1.26 (m, 2H).

Example 19

Compounds described in the Tables 48 and 49 as the Example No. 19 and corresponding to respective starting raw materials were synthesized from 2-(2-(4-(6-(cis-4-aminocyclohexyloxy)-2-naphthyloxy)-phenyl)acetylamino)benzoic acid methyl ester and 2-(2-(4-(7-(cis-4-aminocyclohexyloxy)-2-naphthyloxy)phenyl)acetylamino)benzoic acid methyl ester obtained by the Example 18 by the method similar to the Example 7. The yields and ¹H-NMR data are shown in the Tables 48 and 49.

Example 20 Synthesis of 2-(2-(4-(6-(cis-4-(benzoylamino)cyclohexyloxy)-2-naphthyloxy)-phenyl)acetyl amino)benzoic acid (compound No. 96)

 

Step 1

A reactor was charged with 358 μl (1.7 eq, 179 μmol) of 0.5M triethylamine-chloroform solution containing 420 μl (105 μmol, 50 mg) of 2-(2-(4-(4-(cis-4-aminocyclohexyloxy)phenoxy)phenyl)acetylamino)benzoic acid methyl ester (0.25M-CHCl₃) obtained by the Example 17, benzoyl chloride (1.5 eq, 22 mg) was added thereto and the mixture was stirred for 2.5 hours. After completing the reaction, 139 mg (157.5 μmol) of an aminomethylated polystyrene resin (product of Novabiochem) was added to the system and stirred for 12 hours. The solution was put on a Silica cartridge (product of Waters) and developed with a hexane/ethyl acetate mixture (1/2) and the obtained solution was distilled to remove the solvent.

Step 2

The compound obtained by the step 1 was dissolved in a mixture of tetrahydrofuran (1 ml) and methanol (0.5 ml), 4N lithium hydroxide solution (0.25 ml) was added thereto and the mixture was stirred over a night. After completing the reaction, the product was acidified with 6N-hydrochloric acid (0.25 ml), water (1 ml) was added, the obtained mixture was extracted with ethyl acetate (2 ml×3) and the organic layer was passed through a sodium sulfate cartridge (product of Waters). The solvent was distilled out and the residue was dried in a desiccator. The compound was identified from the molecular weight using LC-MS and the obtained molecular weight was consistent with the above structure. The data are described in the Table 76.

Example 21

The compounds described as the Example No. 21 in the Tables 75 to 89 were synthesized by a method similar to the Example 20 using corresponding substrates. The compounds were identified by the molecular weight using LC-MS and the results were consistent with the structures. The results are shown in the Tables 75 to 89.

Example 22 Synthesis of 2-(2-(4-(4-(cis-4-(2-pyridylcarbonylamino)cyclohexyloxy)-phenoxy)phenyl)acetylamino)benzoic acid (Compound No. 254)

 

Step 1

2-(2-(4-(4-(cis-4-Aminocyclohexyloxy)phenoxy)phenyl)acetylamino)benzoic acid methyl ester (47 mg, 0.1 mmol) obtained by the Example 17 was dissolved in preparatorily dried chloroform (0.5 ml) and the solution was added with HOBT (0.12 mmol, 16 mg) and picolinic acid (0.12 mmol, 15 mg). t-BuOH (0.4 ml) and chloroform (1.3 ml) were poured into the mixture, EDCl (0.12 mmol, 23 mg) was added thereto and the mixture was stirred over a night at room temperature. The obtained solution was put on a Silica cartridge (product of Waters) and developed with a mixture of hexane/ethyl acetate (1/2), and the obtained solution was distilled to remove the solvent.

Step 2

The compound obtained by the step 1 was dissolved in a mixture of tetrahydrofuran (1 ml) and methanol (0.5 ml), and the solution was added with 4N aqueous solution of lithium hydroxide (0.25 ml) and stirred over a night. After completing the reaction, the product was acidified with 6N hydrochloric acid (0.25 ml), added with water (1 ml) and extracted with ethyl acetate (2 ml×3), and the organic layer was passed through a sodium sulfate cartridge (product of Waters). The solvent was distilled off and the residue was dried in a desiccator. The obtained compound was identified by the molecular weight using LC-MS and the result was consistent with the above structure. The data are shown in the Table 83.

Example 23

The compounds described as the Example No. 23 in the Tables 75 to 89 were synthesized by a method similar to the Example 22 using corresponding substrates. The compounds were identified by the molecular weight using LC-MS and the results were consistent with the above structures. The results are shown in the Tables 75 to 89.

Example 24 Synthesis of 2-(2-(4-(4-(N-acetyl-4-piperidyloxy)phenoxy)phenyl)-acetylamino)benzoic acid (Compound No. 78)

 

Step 1

A reactor was charged with 2-(2-(4-(4-(4-piperidyloxy)phenoxy)-phenyl)acetylamino)benzoic acid methyl ester (120 mg, 0.26 mmol), preparatorily dried dichloromethane was poured thereto, triethylamine (47 μl, 1.3 eq., 338 μmol) was charged to the reactor, subsequently acetyl chloride (24 μl, 1.3 eq., 338 μmol) was added thereto and the mixture was stirred for 2.5 hours. After completing the reaction, the reaction product was added with water, extracted with dichloromethane and dried with sodium sulfate, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography.

Step 2

The compound produced by the step 1 was dissolved in the mixture of tetrahydrofuran (1 ml) and methanol (0.5 ml), mixed with 4N aqueous solution of lithium hydroxide (0.25 ml) and stirred over a night. After completing the reaction, the product was acidified with 6N hydrochloric acid (0.25 ml), extracted with ethyl acetate and dried with sodium sulfate. The solvent was distilled out and the residue was dried in a desiccator. The produced compound was identified by the molecular weight using LC-MS and the result was consistent with the above structure. The data are shown in the Table 76.

Example 25

The compounds described as the Example No. 25 in the Tables 75 to 89 were synthesized by a method similar to the Example 24 using corresponding substrates. The compounds were identified by the molecular weight using LC-MS and the results were consistent with the structures. The results are shown in the Tables 75 to 89.

Example 26

The compound of the compound No. 17 was synthesized by using the compound No. 26 of the Table 1 by a method similar to the Referential Example 23. The compound was identified by ¹H-NMR, and the results are shown in the Table 48.

Example 27 Synthesis of 2-(2-(4-(4-(t-butoxycarbonylmethoxy)phenoxy)phenyl)-acetylamino)benzoic acid methyl ester

 

Potassium carbonate (162 mg) was added to 221 mg of 2-(2-(4-(4-hydroxyphenyloxy)phenyl)acetylamino)benzoic acid methyl ester obtained by the Reference Example 24, the mixture was suspended in dried DMF (5 ml), t-butyl bromoacetate (130 μl) was added little by little to the suspension at room temperature, and the mixture was stirred as it is over a night at room temperature. After completing the reaction, DMF was distilled out under reduced pressure and the product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of potassium bisulfate and dried with anhydrous magnesium sulfate. After removing the solvent by distillation, the residue was purified by silica gel column chromatography (developing liquid: hexane:ethyl acetate 4:1 to 1:1) to obtain 174 mg of the subject compound. The ¹H-NMR of the compound was consistent with the above structure.

Yield: 60%.

¹H-NMR (CDCl₃); δ 11.04 (brs, 1H), 8.71 (dd, 1H, J=8.6, 1.0 Hz), 7.91 (dd, 1H, J=8.2 Hz, 1.7 Hz), 7.52 (ddd, 1H, J=8.6, 7.3, 1.7 Hz), 7.31 (d, 2H, J=8.6 Hz), 7.06 (ddd, 1H, J=8.2, 7.3, 1.0 Hz), 6.98 (d, 2H, J=9.2 Hz), 6.96 (d, 2H, J=8.6 Hz), 6.86 (d, 2H, J=9.2 Hz), 4.49 (s, 2H), 3.87 (s, 3H), 3.73 (s, 2H), 1.49 (s, 9H).

Example 28 Synthesis of 2-(2-(4-(4(hydroxycarbonylmethoxy)phenoxy)phenyl)-acetylamino)benzoic acid methyl ester

 

TFA (4 ml) was added to 2-(2-(4-(4-(t-butoxycarbonylmethoxy)-phenoxy)phenyl)acetylamino)benzoic acid methyl ester produced by the Example 27 and the mixture was stirred for 2 hours at room temperature. After the reaction, TFA was distilled out under reduced pressure and the product was dissolved in ethyl acetate. The organic layer was washed with water and dried with anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure to quantitatively obtain the subject compound (164 mg). The result of ¹H-NMR was consistent with the above structure.

Yield: 100%.

¹H-NMR (CDCl₃); δ 11.09 (brs, 1H), 9.91 (brs, 1H), 8.68 (dd, 1H, J=8.6 Hz), 7.98 (dd, 1H, J=8.2, 1.7 Hz), 7.52 (ddd, 1H, J=8.6, 7.3, 1.7 Hz), 7.31.(d, 2H, J=8.6 Hz), 7.08 (dd, 1H, J=8.2, 7.3 Hz), 6.99 (d, 2H, J=9.2 Hz), 6.96 (d, 2H, J=8.6 Hz), 6.89 (d, 2H, J=9.2 Hz), 4.65 (s, 2H), 3.86 (s, 3H), 3.76 (s, 2H).

Example 29 Synthesis of 2-(2-(4-(4-(piperidinamidomethyloxy)phenoxy)phenyl)-acetylamino)benzoic acid methyl ester (methyl ester of the Compound No. 42)

 

2-(2-(4-(4-(Hydroxycarbonylmethoxy)phenoxy)phenyl)acetylamino)benzoic acid methyl ester (164 mg, 0.377 mmol) obtained by the Example 28 was suspended in methylene chloride (10 ml) and oxalyl chloride (34 μl) was added to the suspension at room temperature. The product was changed to transparent brown color under foaming by the addition of about 2 drops of dried DMF. After stirring at room temperature for 2 hours, the solvent and excess oxalyl chloride were distilled off under reduced pressure, and the residue was dissolved in methylene chloride (10 ml). Piperidine (35 μl) and triethylamine (54 μl) were added to the solution and reacted over a night at room temperature. The product was extracted with methylene chloride, and the organic layer was washed with saturated aqueous solution of potassium bisulfate and dried with anhydrous magnesium sulfate. The product was subjected to silica gel column chromatography (developing liquid; hexane:ethyl acetate=1:1) to obtain the subject compound (118 mg, 0.234 mg). The result of ¹H-NMR was consistent with the above structure.

Yield: 62%.

¹H-NMR (CDCl₃); δ 11.04 (brs, 1H), 8.71 (dd, 1H, J=8.6 Hz, 1.0 Hz), 7.99 (dd, 1H, J=7.9 Hz, 1.7 Hz), 7.52 (ddd, 1H, J=8.6, 7.3, 1.7 Hz), 7.31 (dd, 2H, J=8.6, 2.0 Hz), 7.06 (ddd, 1H, J=7.9, 7.3, 1.0 Hz), 6.98 (d, 2H, J=9.2, 2.6 Hz), 6.96 (dd, 2H, J=9.2, 2.6 Hz), 6.92 (dd, 2H, J=8.6, 2.0 Hz), 4.66 (s, 2H), 3.87 (S, 3H), 3.72 (S, 2H), 3.55-3.58 (br, 2H), 3.46-3.50 (br, 2H), 1.57-1.68 (br, 6H).

Example 30

The compound of the compound No. 42 of the Table 2 was synthesized by a method similar to the Example 7 using the compound obtained by the Example 29. The result of ¹H-NMR was consistent with the above structure. The data are shown in the Table 55.

Example 31 Synthesis of 2-(2-(4-(4-(3-(tert-butoxycarbonylamino)benzyloxy)phenoxy)-phenyl)acetylamino)benzoic acid methyl ester

 

2-(2-(4-(4-Hydroxyphenoxy)phenyl)acetylamino)benzoic acid methyl ester obtained by the Reference Example 24 (315 mg, 0.83 mmol) was dissolved in 20 ml of methylene chloride-THF mixture (1:1 v/v), added with 3-(tert-butoxycarbonylamino)benzyl alcohol (465 mg, 2.1 mmol), 1,1′-azobis(N,N′-dimethylformamide) (359 mg, 2.08 mmol) and tri-n-butyl phosphine (520 ml, 2.1 mmol) and the reaction mixture was stirred over a night. After completing the reaction, the solvent was removed under reduced pressure and the obtained crude residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate 75:25 v/v) to obtain the subject compound (404 mg, 0.693 mmol) in the form of a colorless gummy substance. The result of ¹H-NMR was consistent with the above structure.

Yield: 83%.

¹H-NMR (CDCl₃); δ 11.03 (brs, 1H), 8.72 (dd, 1H, J=1.08, 8.64 Hz), 7.99 (dd, 1H, J=1.89, 8.10 Hz), 7.55-7.49 (m, 2H), 7.34-7.26 (m, 6H), 7.04-6.90 (m, 6H), 7.51 (brs, 1H), 5.02 (s, 2H), 3.87 (s, 3H), 3.73 (s, 2H), 1.52 (s, 9H).

Example 32

The following compound was synthesized by a method similar to the Example 31 using the corresponding substrate. The result of ¹H-NMR was consistent with the structure.

2-(2-(4-(4-(4-(tert-Butoxycarbonylamino)benzyloxy)phenoxy)phenyl)-acetylamino)benzoic acid methyl ester

Yield: 46%.

¹H-NMR (CDCl₃); δ 11.03 (brs, 1H), 8.71 (d, 1H, J=7.56 Hz), 7.99 (dd, 1H, J=1.62, 7.83 Hz), 7.51 (dt, 1H, J=1.35, 8.64 Hz), 7.34-7.30 (m, 4H), 7.28-7.25 (m, 2H), 7.07 (t, 1H, J=8.37 Hz), 7.00-6.90 (m, 6H), 6.49 (s, 1H), 4.98 (s, 2H), 3.87 (s, 3H), 3.72 (s, 2H), 1.52 (s, 9H).

Example 33 Synthesis of 2-(2-(4-(4-(2-(tert-butoxycarbonylamino)benzyloxy)phenoxy)-phenyl)acetylamino)benzoic acid methyl ester

 

2-(2(4-(4-Hydroxyphenoxy)phenyl)acetylamino)benzoic acid methyl ester (300 mg, 0.82 mmol) obtained by the Reference Example 24 was dissolved in anhydrous N-dimethylformamide (10 ml), added with sodium hydride (30 mg, abt. 60%), stirred for 15 minutes and added with N-tert-butoxycarbonyl-2-bromomethylaniline (540 mg, 1.9 mmol). The reaction mixture was stirred over a night at room temperature, water (150 ml) was added thereto, the mixture was extracted with ethyl acetate (50 ml×2) and washed with water (100 ml×3), the organic solvent was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate 75:25 v/v) to obtain the subject compound (234 mg, 0.402 mmol) in the form of a colorless gummy substance. The result of ¹H-NMR was consistent with the above structure.

Yield: 49%.

¹H-NMR (CDCl₃); δ 11.05 (brs, 1H), 8.72 (dd, 1H, J=1.03, 8.37 Hz), 7.99 (dd, 1H, J=1.62, 8.10 Hz), 7.93 (d, 1H, J=8.37 Hz), 7.52 (dt, 1H, J=1.62, 7.29 Hz), 7.42-7.25 (m, 6H), 7.09-6.94 (m, 7H), 5.05 (s, 2H), 3.89 (s, 3H), 3.73 (s, 2H), 1.51 (s, 9H).

Example 34 Synthesis of 2-(2-(4-(4-(3-(acetylamino)benzyloxy)phenoxy)phenyl)-acetylamino)benzoic acid methyl ester (methyl ester of the Compound No. 50)

 

2-(2-(4-(4-(3-(tert-Butoxycarbonylamino)benzyloxy)phenoxy)-phenyl)acetylamino)benzoic acid methyl ester (155 mg, 0.266 mmol) obtained by the Example 31 was dissolved in 4N hydrochloric acid-1,4-dioxane solution (5.0 ml) and stirred for 30 minutes at room temperature. The solvent was quickly removed under reduced pressure and the residue was dried under reduced pressure. The dried residue was dissolved in methylene chloride (10 ml) and triethylamine (0.11 ml, 0.789 mmol), added with acetyl chloride (0.025 ml) and stirred for a night at room temperature. After completing the reaction, the reaction liquid was added with water (100 ml) and immediately extracted with ethyl acetate (20 ml×2). The collected ethyl acetate layer was dried with anhydrous magnesium sulfate and filtered, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel chromatography (elution, hexane:ethyl acetate 6:4 v/v) to obtain the subject compound (110 mg, 0.215 mmol) in the form of a colorless gummy substance. The result of ¹H-NMR was consistent with the above structure.

Yield: 81%.

¹H-NMR (CDCl₃); δ 11.04 (brs, 1H), 8.71 (d, 1H, J=8.37 Hz), 7.99 (dd, 1H, J=1.62, 8.10 Hz), 7.60 (brs, 1H), 7.53 (dd, 2H, J=1.62, 8.64 Hz), 7.45-7.23 (m, 4H), 7.17 (d, 1H, J=7.56 Hz), 7.06 (t, 1H, J=7.02 Hz), 7.00-8.89 (m, 6H), 5.02 (s, 2H), 3.87 (s, 3H), 3.72 (s, 2H), 2.17 (s, 3H).

Example 35

The following compounds were synthesized by a method similar to the Example 34 using the compounds obtained by the Examples 32 and 33 and reacting with respective corresponding substrates. The results of ¹H-NMR were consistent with the structures.

2-(2-(4-(4-(3-(Benzoylamino)benzyloxy)phenoxy)phenyl)acetylamino)benzoic acid methyl ester (methyl ester of the Compound No. 51)

Yield: 49%.

¹H-NMR (CDCl₃); δ 11.03 (brs, 1H), 8.70 (d, 1H, J=8.37 Hz), 8.16 (brs, 1H), 7.99 (dd, 1H, J=1.62, 8.10 Hz), 7.88 (dd, 2H, J=1.62, 6.76 Hz), 7.78 (brs, 1H), 7.64 (d, 1H, J=7.56 Hz), 7.55-7.20 (m, 9H), 7.09-6.91 (m, 6H), 5.05 (s, 2H), 3.86 (s, 3H).

2-(2-(4-(4-(2-(Acetylamino)benzyloxy)phenoxy)phenyl)acetylamino)benzoic acid methyl ester (methyl ester of the Compound No. 46)

Yield: 68%.

¹H-NMR (CDCl₃); δ 11.06 (brs, 1H), 8.71 (d, 1H, J=8.64 Hz), 8.14 (brs, 1H), 8.07 (d, 1H, J=8.37 Hz), 8.00 (dd, 1H, J=1.62, 8.10 Hz), 7.54 (dt, 1H, J=1.62, 8.91 Hz), 7.38-7.26 (m, 5H), 7.16-7.93 (m, 7H), 5.06 (s, 2H), 3.87 (s, 3H), 3.73 (s, 2H), 2.13 (s, 3H).

2-(2-(4-(4-(2-(Methoxycarbonylamino)benzyloxy)phenoxy)phenyl)-acetylamino)benzoic acid methyl ester (methyl ester of the compound No. 48)

Yield: 80%.

¹H-NMR (CDCl₃); δ 11.04 (brs, 1H), 8.72 (d, 1H, J=8.73 Hz), 8.00 (d, 1H, J=8.10 Hz), 7.52 (t, 1H, J=8.00 Hz), 7.40-7.90 (m, 13H), 6.78-6.60 (m, 1H), 5.00 (s, 2H), 3.86 (s, 3H), 3.73 (s, 2H), 3.59 (s, 3H).

2-(2-(4-(4-(2-(Benzoylamino)benzyloxy)phenoxy)phenyl)acetylamino)benzoic acid methyl ester (methyl ester of the Compound No. 49)

Yield: 63%.

¹H-NMR (CDCl₃); δ 11.06 (brs, 1H), 9.16 (brs, 1H), 8.73 (d, 1H, J=8.37 Hz), 8.33 (d, 1H, J=8.37 Hz), 8.11 (d, 1H, J=7.12 Hz), 8.00 (dd, 2H, J=1.89, 6.21 Hz), 7.88-7.60 (m, 4H), 7.60-7.15 (m, 7H), 7.10-6.91 (m, 5H), 5.16 (s, 2H), 3.86 (s, 3H), 3.73 (s, 2H).

Example 36

The compounds described in the Table 90 as example No. 36 were synthesized by a method similar to the Example 7 using the corresponding substrates obtained by the Examples 34 and 35. The produced compounds were confirmed by LC-MS and the results were consistent with the structures. The results are shown in the Table 90.

Example 37 Synthesis of 2-((4-(6-(3-aminopropoxy)-2-naphthyloxy)phenyl)-carbonylamino)benzoic acid (Compound No. 33)

 

2-((4-(6-(3-(tert-Butoxycarbonylamino)propoxy)-2-naphthyloxy)-phenyl)carbonylamino)benzoic acid (compound No. 31, 50 mg, 0.09 mmol) obtained by the Example 8 was dissolved in 3 ml of 4N hydrochloric acid-1,4-dioxane solution and 2.5 ml of 1,4-dioxane, stirred at room temperature for 5.5 hours and at 50 to 60° C. for 7 hours (3 ml of 4N hydrochloric acid-1,4-dioxane solution was added 3 hours after heating) and further stirred at room temperature for a night. After completing the reaction, the reaction liquid was concentrated and the crude product was recrystallized from ethanol (4 ml) to obtain the subject compound (14.5 mg, 0.0317 mmol) in the form of white granular crystal. The result of ¹H-NMR was consistent with the structure.

Yield: 35%.

¹H-NMR (DMSO-d₆); δ 2.07 (quint, J=5.9 Hz, 2H), 2.95-3.10 (m, 2H), 4.18 (t, J=5.9 Hz, 2H), 7.15-7.23 (m, 4H), 7.33 (dd, J=2.3, 8.9 Hz, 1H), 7.38 (d, J=2.0 Hz, 1H), 7.57 (d, J=2.6 Hz, 1H), 7.61-7.64 (m, 1H), 7.82 (d, J=8.9 Hz, 1H), 7.91 (d, J=9.2 Hz, 1H), 7.98 (d, J=8.9 Hz, 2H), 8.04 (d, J=8.3 Hz, 1H), 8.69 (d, J=8.6 Hz, 1H).

TABLE 44 Compound Yield Example No. (%) ¹H-NMR(CDCl₃): δ No. 1 68 ¹H-NMR (DMSO-d₆); δ 1.13(t, J=6.9Hz, 3H), 3.52(q, 7 J=6.9Hz, 2H), 3.73-3.76(m, 4H), 4.18(t, J=4.3, 2H), 7.02(d, J=8.6Hz, 2H), 7.10-7.18(m, 2H), 7.22-7.26(m, 1H), 7.34-7.39(m, 4H), 7.57(t, J=8.9Hz, 1H), 7.73(d, J=8.9Hz, 1H), 7.83(d, J=8.9Hz, 1H), 7.95(dd, J=1.7, 7.9Hz, 1H), 8.50(d, J=8.3Hz, 1H), 11.12(br.s, 1H), 13.57(br.s, 1H). 1 80 1.27(t, J=6.9Hz, 3H), 3.64(q, J=6.9Hz, 2H), 3.75(s, 2H), 5 methyl 3.84-3.88(m, 2H), 3.88(s, 3H), 4.24(t, J=4.6Hz, 2H), ester 7.02-7.25(m, 6H), 7.31-7.37(m, 3H), 7.50-7.57(m, 1H), 7.60(d, J=8.9Hz, 1H), 7.69(d, J=8.9Hz, 1H), 8.01(dd, J=1.7, 8.3Hz, 1H), 8.73(dd, J=1.0, 8.6Hz, 1H), 11.07(br.s, 1H). 2 73 ¹H-NMR (DMSO-d₆); δ 1.91(quint, J=6.3Hz, 2H), 8 3.20(q, J=6.3Hz, 2H), 3.75(s, 2H), 4.08(t, J=6.3Hz, 2H), 5.01(s, 2H), 7.02(d, J=8.6Hz, 2H), 7.07-7.16(m, 2H), 7.23-7.39(m, 10H), 7.57(t, J=8.6Hz, 1H), 7.72(d, J=8.9Hz, 1H), 7.83(d, J=8.9Hz, 1H), 7.95(dd, J=1.7, 7.9Hz, 1H), 8.50(d, J=8.3Hz, 1H), 11.13(br.s, 1H), 13.57(br.s, 1H). 2 69 11.08(brs, 1H), 8.72(t, 1H, J=8.3, 1.3Hz), 8.01(dd, 1H, 6 methyl J=8.3, 1.3Hz), 7.69(d, 1H, J=8.9Hz), 7.60(d, 1H, J=9.6Hz), ester 7.53(t, 1H, J=8.3Hz), 7.37-7.31(m, 8H), 7.25-7.22(m, 1H), 7.12-7.03(m, 5H), 5.11(s, 2H), 4.14(t, 2H, J=6.9Hz), 3.89(s, 3H), 3.75(s, 2H), 3.48(q, 2H, J=6.6Hz), 2.10-2.05(m, 2H). 3 69 ¹H-NMR (DMSO-d₆); δ 1.35-1.65(m, 4H), 1.77(quint, 8 J=6.6Hz, 2H), 2.24(t, J=7.3Hz, 2H), 3.74 (s, 2H), 4.05(t, J=6.6Hz, 2H), 7.02(d, J=8.6Hz, 2H), 7.10-7.15(m, 2H), 7.23(dd, J=2.6, 8.9Hz, 1H), 7.32-7.38(m, 4H), 7.56(t, J=8.6Hz, 1H), 7.72(d, J=9.2Hz, 1H), 7.83(d, J=9.2Hz, 1H), 7.95(dd, J=1.7, 7.9Hz, 1H), 8.50(d, J=7.6Hz, 1H), 11.28(br.s, 1H). 3 100 11.07(brs, 1H), 8.73(dd, 1H, J=8.6, 1.0Hz), 8.01(dd, 1H, 6 methyl J=7.9, 1.7Hz), 7.69(d, 1H, J=8.9Hz), 7.60(d, 1H, J=9.6Hz), ester 7.57-7.50(m, 1H), 7.37-7.31(m, 3H), 7.23(dd, 1H, J=8.9, 2.6Hz), 7.15-7.02(m, 5H), 4.14(q, 2H, J=7.3Hz), 4.07(t, 2H, J=6.6Hz), 3.88(s, 3H), 3.75(s, 2H), 2.35(t, 2H, J=7.3Hz), 1.95-1.80(m, 2H), 1.80-1.65(m, 2H), 1.65-1.45(m, 2H), 1.26(t, 3H, J=7.3Hz).  

TABLE 45 4 53 ¹H-NMR(DMSO-d₆); δ 13.57(brs, 2H), 8 11.17(s, 1H), 11.13(s, 1H), 8.51(d, 1H, J = 3.3 Hz), 8.48(d, 1H, J = 3.3 Hz), 7.98-7.93(m, 2H), 7.82 (d, 1H, J = 8.9 Hz), 7.72(d, 1H, J = 9.2 Hz), 7.61-7.54(m, 2H), 7.38-7.33(m, 4H), 7.23(dd, 1H, J = 8.9, 2.6 Hz), 7.16-7.11(m, 3H), 7.02(d, 2H, J = 8.6 Hz), 4.14(t, 2H, J = 6.3 Hz), 3.75(s, 2H), 2.61(t, 2H, J = 6.9 Hz), 2.12(qint, 2H, J = 6.9 Hz). 4 41 11.05(brs, 1H), 11.08(brs, 1H), 8.74(dd, 1H, J = 8.6, 6 methyl 1.0 Hz), 8.73(dd, 1H, J = 8.3, 1.0 Hz), 8.01 ester 7.67(d, 1H, J = 8.9 Hz), 7.60-7.50(m, 3H), methyl 4.18(t, 2H, 7.38-7.31(m, 3H), 7.22(dd, 1H, ester J = 8.9, 2.6 Hz),7.15-7.02(m, 6H), 4.18(t, 2H, J = 6.3 Hz), 3.88(s, 3H), 3.87(s, 3H), 3.75(s,2H), 2.71(t, 2H, J = 6.9 Hz), 2.30 (quint, 2H, J = 6.9 Hz). 5 86 ¹H-NMR(DMSO-d₆); δ 1.91(quint, J = 6.3 Hz, 2H), 8 3.59(t, J = 6.3 Hz, 2H), 3.75(s, 2H), 4.13 (t, J = 6.3 Hz, 2H), 5.16(br.s, 1H), 7.02 (d, J = 8.6 Hz, 2H), 7.10-7.16(m, 2H), 7.24 (dd, J = 2.6, 8.6 Hz, 1H), 7.33-7.39 (m, 4H), 7.57(t, J = 8.9 Hz, 1H), 7.72(d, J = 8.9 Hz, 1H), 7.84 (d, J = 9.2 Hz, 1H), 7.95(dd, J = 1.3, 8.3 Hz, 1H), 8.49(d, J = 8.6 Hz, 1H), 11.72(s, 1H), 14.17(br.s, 1H). 5 44 11.08(brs, 1H), 8.73(dd, 1H, J = 8.6, 1.3 Hz), 8.01 6 methyl (dd, 1H, J = 8.2, 1.7 Hz), 7.70(d, 1H, J = 8.9 Hz), ester 7.61(d, 1H, J = 8.6 Hz), 7.53(t, 1H, J = 8.6 Hz), 7.37- 7.32(m, 3H), 7.25-7.22(m, 1H), 7.15-7.03(m, 5H), 4.24 (t, 2H, J =]5.9 Hz), 3.99-3.87(m, 5H), 3.75 (s, 2H), 2.12(quint, 2H, J = 5.9 Hz). 6 50 ¹H-NMR(DMSO-d₆); δ 3.72(s, 2H), 5.68(s, 2H), 8 7.02(s,J = 8.6 Hz, 2H), 7.08(t, J = 7.5 Hz, 1H), 7.21-7.27(m, 2H), 7.36-7.39(m, 4H), 7.49 (t, J = 6.9 Hz, 1H), 7.56-7.61(m, 2H), 7.68-7.81 (m, 3H), 7.96(dd, J = 7.9, 1.5 Hz, 1H), 8.07 (d, J = 8.0 Hz, 2H), 8.50(d, J = 8.0 Hz, 1H), 11.91(brs, 1H). 6 95 11.08(brs, 1H), 8.72(d, 1H, J = 8.0 Hz), 8.06-7.98 6 methyl (m, 3H), 69-7.61(m, 3H), 7.55-7.49(m, 3H), ester 7.37-7.32(m, 7.26-7.21(m, 2H), 7.13-7.05(m, 4H), 5.38 (s, 2H), 3.88(s, 3H) 3.75(s, 2H).  

TABLE 46  7 63 Hydrochloride: ¹H-NMR (DMSO-d₆); δ 3.18(4H, brs), 8 3.43(2H, s br), 3.76(2H, s), 3.83(4H, t-like, J=4.6Hz), 4.45(2H, t-like, J=5.0Hz), 7.03(2H, d, J=8.6Hz), 7.14(1H, t-like, J=7.5Hz), 7.20(1H, dd, J=8.9, 2.3Hz), 7.27(1H, dd, J=8.9, 2.7Hz), 7.37-7.41(4H, m), 7.57(1H, t, J=8Hz), 7.77(1H, d, J=9.2Hz), 7.86(1H, d, J=8.9Hz), 7.96(1H, dd, J=7.9, 1.3Hz), 8.52(1H, d, J=8.3Hz), 11.18(1H, brs).  7 21 11.08(brs, 1H), 8.73(dd, 1H, J=8.6, 0.7Hz), 8.00(dd, 1H, 6 methyl J=8.1, 1.3Hz), 7.69(d, 1H, J=8.9Hz), 7.60(d, 1H, J=9.6Hz), ester 7.53(t, 1H, J=8.5Hz), 7.37-7.03(m, 9H), 4.22(t, 2H, J=5.6Hz), 3.89(s, 3H), 3.75(t, 4H, J=4.6Hz), 3.75(s, 2H), 2.87(t, 2H, J=5.6Hz), 2.62(t, 4H, J=4.6Hz).  9 40 ¹H-NMR (DMSO-d₆); δ 13.58(brs, 1H), 11.16(s, 1H), 8 8.53(d, 1H, J=8.6Hz), 7.96(dd, 1H, J=7.9, 1.7Hz), 7.84(d, 1H, J=8.6Hz), 7.78(d, 1H, J=8.9Hz), 7.58(m, 1H), 7.41(d, 2H, J=8.6Hz), 7.26-7.02(m, 7H), 4.53(brs, 1H), 4.11(t, 2H, J=6.3Hz), 3.78(s, 2H), 3.58(t, 2H, J=6.0Hz), 1.90(quint, 2H, J=6.3Hz).  9 47 11.10(brs, 1H), 8.72(dd, 1H, J=8.58, 0.99Hz), 8.00(dd, 6 methyl 1H, J=8.24, 1.65Hz), 7.71(d, 1H, J=8.25Hz), 7.68(d, 1H, ester J=7.91Hz), 7.52(ddd, 1H, J=8.58, 7.25, 1.65Hz), 7.37(d, 2H, J=8.57Hz), 7.20(d, 1H, J=2.31Hz), 7.12-6.99(m, 6H), 4.18(t, 2H, J=5.93Hz), 3.88(s, 3H), 3.88(t, 2H, J=4.95Hz), 3.75(s, 2H), 2.08(m, 2H). 10 81 ¹H-NMR (DMSO-d₆); δ 13.56(brs, 1H), 11.19(s, 1H), 8 8.54(d, 1H, J=8.6Hz), 7.96(dd, 1H, J=7.9, 1.7Hz), 7.85(d, 1H, J=8.6Hz), 7.79(d, 1H, J=8.9Hz), 7.57(m, 1H), 7.41(d, 2H, J=8.6Hz), 7.23-7.04(m, 7H), 4.15(t, 2H, J=4.6Hz), 3.78(s, 2H), 3.73(t, 2H, J=4.6Hz), 3.51(q, 2H, J=7.0Hz), 1.14(t, 3H, J=7.0Hz). 10 93 11.10(brs, 1H), 8.73(d, 1H, J=8.25Hz), 7.99(dd, 1H, 6 methyl J=7.91, 1.65Hz), 7.70(d, 1H, J=8.25Hz), 7.67(d, 1H, ester J=8.24Hz), 7.52(ddd, 1H, J=8.58, 7.25, 1.32Hz), 7.37(d, 2H, J=8.57Hz), 7.21(d, 1H, J=1.98Hz), 7.13-7.03(m, 5H), 6.99(d, 1H, J=2.64Hz), 4.18(t, 2H, J=4.61Hz), 3.87(s, 3H), 3.82(t, 2H, J=4.62Hz), 3.75(s, 2H), 3.60(q, 2H, J=6.93Hz), 1.24(t, 3H, J=6.93Hz).  

TABLE 47 11 33 ¹H-NMR (DMSO-d₆); δ 14.05(brs, 1H), 8.46(d, 1H, J=8.2Hz), 11 7.95(dd, 1H, J=7.8, 1.5Hz), 7.82(d, 1H, J=8.9Hz), 7.74(d, 1H, J=9.2Hz), 7.40(d, 2H, J=8.6Hz), 7.30-7.20(m, 3H), 7.14-6.94(m, 5H), 4.13(t, 2H, J=5.5Hz), 3.64(s, 2H), 3.07(brm, 4H), 2.74(brm, 2H), 2.70(brs, 4H). 11 48 11.10(brs, 1H), 8.73(dd, 1H, J=8.58, 0.99Hz), 8.01(dd, 10 methyl 1H, J=8.35, 1.65Hz), 7.71(d, 1H, J=8.58Hz), 7.68(d, 1H, ester J=7.91Hz), 7.53(ddd, 1H, J=8.57, 7.26, 1.32Hz), 7.38(d, 2H, J=8.90Hz), 7.21(d, 1H, J=1.98Hz), 7.13-7.04(m, 5H), 6.99(d, 1H, J=2.31Hz), 4.18(t, 2H, J=5.94Hz), 3.89(s, 3H), 3.76(s, 2H), 2.92(t, 4H, J=4.62Hz), 2.84(t, 2H, J=5.94Hz), 2.56(brm, 4H). 12 32 ¹H-NMR (DMSO-d₆); δ 8.48(d, 1H, J=8.6Hz), 7.95(d, 11 1H, J=7.9Hz), 7.84(d, 1H, J=8.9Hz), 7.78(d, 1H, J=8.9Hz), 7.66-7.57(m, 1H), 7.45-7.38(m, 2H), 7.28-7.02(m, 7H), 4.17(t, 2H, J=5.7Hz), 3.72(s, 2H), 3.61-3.56(m, 8H), 2.75(t, 2H, J=5.7Hz). 12 78 11.11(brs, 1H), 8.73(dd, 1H, J=8.58, 0.66Hz), 8.01(dd, 10 methyl 1H, J=8.25, 1.65Hz), 7.72(d, 1H, J=8.25Hz), 7.69(d, 1H, ester J=7.91Hz), 7.53(ddd, 1H, J=8.57, 7.26, 1.65Hz), 7.38(d, 2H, J=8.57Hz), 7.21(d, 1H, J=2.31Hz), 7.13-7.04(m, 5H), 6.99(d, 1H, J=2.31Hz), 4.19(t, 2H, J=5.93Hz), 3.89(s, 3H), 3.76(s, 2H), 3.74(t, 4H, J=4.62Hz), 2.85(t, 2H, J=5.94Hz), 2.60(t, 4H, J=4.62Hz). 13 69 ¹H-NMR (DMSO-d₆); δ 8.57(dd, 2H, J=4.5, 1.5Hz), 11 8.48(d, 1H, J=8.3Hz), 7.97(dd, 1H, J=7.9, 1.6Hz), 7.85(t, 2H, J=9.2Hz), 7.65-7.54(m, 2H), 7.47-7.36(m, 5H), 7.24-7.05(m, 5H), 5.27(s, 2H), 3.71(s, 2H). 13 85 11.12(brs, 1H), 8.73(d, 1H, J=8.58Hz), 8.62(dd, 2H, 10 methyl J=4.62, 1.65Hz), 8.01(dd, 1H, J=8.25, 1.65Hz), ester 7.75-7.36(m, 8H), 7.19-7.01(m, 6H), 5.17(s, 2H), 3.89(s, 3H), 3.76(s, 2H). 14 10 ¹H-NMR (DMSO-d₆); δ 13.19(brs, 1H), 8.49(d, 1H, J=7.6Hz), 11 7.97(d, 1H, J=7.9Hz), 7.84(d, 1H, J=8.9Hz), 7.78(d, 1H, J=8.9Hz), 7.37(d, 2H, J=8.6Hz), 7.40-7.33(m, 2H), 7.25(s, 1H), 7.13(dd, 1H, J=8.9, 2.5Hz), 7.05-6.96(m, 2H), 7.05(d, 2H, J=8.6Hz), 4.37(2H, m), 3.67(s, 2H), 3.22(brs, 2H), 2.98(brs, 4H), 1.67(brs, 4H), 1.5-1.4(brs, 2H).  

TABLE 48 14 60 11.10(brs, 1H), 8.73(d, 1H, J=8.25Hz), 8.01(dd, 1H, 10 methyl J=8.25, 1.65Hz), 7.71(d, 1H, J=8.58Hz), 7.68(d, 1H, ester J=8.24Hz), 7.53(dd, 1H, J=8.57, 7.26Hz), 7.37(d, 2H, J=8.24Hz), 7.21(d, 1H, J=1.98Hz), 7.12-7.04(m, 5H), 6.99(d, 1H, J=2.31Hz), 4.18(t, 2H, J=5.93Hz), 3.89(s, 3H), 3.76(s, 2H), 2.81(t, 2H, J=5.94Hz), 2.52(t, 4H, J=4.95Hz), 1.65-1.56(brm, 4H), 1.47-1.43(brm, 2H). 16 100 ¹H-NMR (DMSO-d₆); δ 11.20(brs, 1H), 8.51(d, 1H, J=8.6Hz), 11 7.96(dd, 1H, J=7.6, 1.7Hz), 7.84(d, 1H, J=8.9Hz), 7.73(d, 1H, J=8.9Hz), 7.57(dd, 1H, J=8.6, 7.6Hz), 7.21-7.39(m, 10H), 7.11-7.16(m, 2H), 7.02(d, 2H, J=8.6Hz), 4.52(brs, 3H), 3.75(s, 2H), 3.49(brm, 1H), 2.03-2.09(brm, 4H), 1.47-1.54(m, 4H). 16 29 11.08(brs, 1H), 8.72(dd, 1H, J=8.6, 1.0Hz), 8.00(dd, 1H, 10 methyl J=7.9, 1.7Hz), 7.69(d, 1H, J=8.9Hz), 7.60(d, 1H, J=8.9Hz), ester 7.53(ddd, 1H, J=8.6, 7.3, 1.7Hz), 7.24-7.37(m, 9H), 7.03-7.22(m, 3H), 7.04(d, 2H, J=8.6Hz), 4.57(s, 2H), 4.43(brm, 1H), 3.88(s, 3H), 3.75(s, 2H), 3.54(brm, 1H), 2.14-2.17(brm, 4H), 1.55-1.64(m, 4H). 17 96 ¹H-NMR (DMSO-d₆); δ 13.90(br, 1H), 8.44(d, 1H, J=8.2Hz), 26 7.99(d, 1H, J=7.6Hz), 7.82(d, 1H, J=8.9Hz), 7.74(d, 1H, J=8.9Hz), 7.27-7.37(m, 6H), 7.22(dd, 1H, J=8.9, 2.3Hz), 7.11(d, 1H, J=8.9, 2.3Hz), 7.00(d, 2H, J=8.6Hz), 6.95(d, 1H, J=7.3Hz), 4.59(d, 1H, J=3.6Hz), 4.43(brm, 1H), 3.62(s, 2H), 3.56(brm, 1H), 2.05(brm, 2H), 1.88(brm, 2H), 1.30-1.52(m, 4H). 18 — ¹H-NMR (DMSO-d₆); δ 11.27(brs, 1H), 8.50(d, 1H, 19 J=8.58Hz), 7.99-7.94(m, 3H), 7.83(d, 1H, J=8.90Hz), 7.76(d, 1H, J=8.91Hz), 7.56(d, 1H, J=8.25, 7.59Hz), 7.39-7.10(m, 5H), 7.02(d, 2H, J=8.58Hz), 4.71(br, 1H), 3.75(s, 2H), 3.17(brm, 1H), 2.06-1.91(m, 2H), 1.78-1.60(m, 6H). 18 66 11.07(brs, 1H), 8.72(d, 1H, J=8.41Hz), 8.00(dd, 1H, 18 methyl J=8.08, 1.65Hz), 7.68-7.49(m, 3H), 7.36-7.02(m, 9H), ester 4.58(br, 1H), 3.88(s, 3H), 3.74(s, 2H), 2.80(m, 1H), 2.09-2.04(m, 2H), 1.70-1.46(m, 6H).  

TABLE 49 19 34 ¹H-NMR (DMSO-d₆); δ 13.58(br, 1H), 11.27(brs, 1H), 19 8.51(d, 1H, J=8.25Hz), 7.97-7.80(m, 5H), 7.57(dd, 1H, J=8.25, 7.59Hz), 7.41(d, 2H, J=7.26Hz), 7.26-7.05(m, 5H), 4.68(br, 1H), 3.77(s, 2H), 3. 13(brm, 1H), 2.07-2.02(m, 2H), 1.75-1.60(m, 6H). 19 71 11.10(brs, 1H), 8.72(d, 1H, J=8.58Hz), 7.99(dd, 1H, 18 methyl J=7.91, 1.65Hz), 7.68-7.63(m, 2H), 7.52(dd, 1H, J=7.26, ester 6.92Hz), 7.36(d, 2H, J=8.58Hz), 7.16-6.97(m, 7H), 4.60(br, 1H), 3.87(s, 3H), 3.75(s, 2H), 3.27(m, 1H), 2.21-2.16(m, 2H), 2.02(m, 4H), 1.61(m, 2H). 20 42% ¹H-NMR (DMSO-d₆); δ 9.87(brs, 1H), 8.43(d, 1H, J=8.37Hz), 11 (yield 8.00(d, 1H, J=7.83Hz), 7.82(d, 1H, J=9.45Hz), form 7.75(d, 1H, J=8.91Hz), 7.51(d, 2H, J=7.83Hz), 7.35(d, Ex. 6) 4H, J=8.37Hz), 7.24(m, 4H), 7.11(d, 1H, J=9.45Hz), 6.94(m, 3H), 4.24(t, 2H, J=6.48Hz), 3.59(s, 2H), 3.03(t, 2H, J=6.21Hz), 2.02(s, 3H). 20 — 11.10(brs, 1H), 8.71(d, 1H, J=8.64Hz), 8.23(brs, 1H), 10 methyl 7.99(d, 1H, J=8.10Hz), 7.69-7.02(m, 16H), 4.22(t, 2H, ester J=7.02Hz), 3.87(s, 3H), 3.74(s, 2H), 3.09(t, 2H, J=7.02Hz), 2.12(s, 3H). 21 87 ¹H-NMR (DMSO-d₆); δ 3.36(3H, s), 3.74(2H, t, J=4.6Hz), 8 4.23(2H, t, J=4.6Hz), 7.16-7.21(4H, m), 7.30(1H, dd, J=8.9, 2.3Hz), 7.38(1H, s), 7.49(1H, s), 7.64(1H, t, J=8.6Hz), 7.85(1H, d, J=8.9Hz), 7.90(1H, d, J=8.9Hz), 7.99(2H, d, J=8.6Hz), 8.23(1H, d, J=7.6Hz), 8.73(1H, d, J=8.2Hz), 12.21(1H, brs). 21 44 12.00(brs, 1H), 8.93(d, 1H, J=8.9Hz), 8.23-8.00(m, 3H), 6 methyl 7.75(d, 1H, J=8.9Hz), 7.66(d, 1H, J=8.9Hz), 7.59(t, 1H, ester J=7.9Hz), 7.41(d, 1H, J=2.3Hz), 7.23-7.08(m, 6H), 4.23(t, 2H, J=4.7Hz), 3.92(s, 3H), 3.82(t, 2H, J=4.7Hz), 3.48(s, 3H). 22 82 ¹H-NMR (DMSO-d₆); δ 1.14(3H, t, J=6.9Hz), 3.52(2H, 8 q, J=6.9Hz), 3.76(2H, t, J=4.3Hz), 4.20(2H, t, J=4.3Hz), 7.16-7.22(4H, m), 7.31(1H, dd, J=2.3, 8.9Hz), 7.39(1H, d, J=2.3Hz), 7.57(1H, d, J=2.6Hz), 7.65(1H, dt, J=1.6, 8.6Hz), 7.81(1H, d, J=9.2Hz), 7.90(1H, d, J=8.9Hz), 7.97(2H, d, J=8.6Hz), 8.04(1H, dd, J=7.9, 1.7Hz), 8.69(1H, d, J=7.6Hz), 12.15(1H, s), 13.7(1H, br s).  

TABLE 50 22 61 12.01(brs, 1H), 8.93(d, 1H, J=8.6Hz), 8.10-8.01(m, 3H), 6 methyl 7.76(d, 1H, J=8.9Hz), 7.68-7.58(m, 2H), 7.42(d, 1H, ester J=2.3Hz), 7.25-7.09(m, 6H), 4.26(t, 2H, J=4.6Hz), 3.95(s, 3H), 3.88(t, 2H, J=4.6Hz), 3.65(q, 2H, J=6.9Hz), 1.28(t, 3H, J=6.9Hz). 23 93 ¹H-NMR (DMSO-d₆); δ 1.51-1.61(2H, m), 1.70(2H, 8 quint, J=7.4Hz), 1.83(2H, quint, J=7.6Hz), 2.36(2H, t, J=7.3Hz), 4.10(2H, t, J=6.6Hz), 7.01(1H, t, J=7.3Hz), 7.15-7.37(8H, m), 7.56-7.68(m, 4H), 7.79(1H, d, J=8.6Hz), 7.90(1H, d, J=8.6Hz), 7.98(1H, d, J=8.9Hz), 8.05(1H, d, J=7.9Hz), 8.72(1H, d, J=8.6Hz), 9.86(1H, s br), 12.16(1H, s br). 23 89 12.01(brs, 1H), 8.92(d, 1H, J=8.1Hz), 8.10-8.01(m, 3H), 6 methyl 7.75(d, 1H, J=8.9Hz), 7.67-7.59(m, 2H), 7.50(d, 2H, ester J=7.9Hz), 7.40(t, 1H, J=2.3Hz), 7.32(t, 1H, J=8.3Hz), 7.26-7.08(m, 9H), 4.10(t, 2H, J=6.2Hz), 3.95(s, 3H), 2.42(t, 2H, J=7.3Hz), 1.94-1.80(m, 4H), 1.68-1.58(m, 2H). 24 88 ¹H-NMR (DMSO-d₆); δ 3.39(2H, t, J=5.6Hz), 4.06(2H, 8 t, J=5.6Hz), 4.98(2H, s), 7.09-7.16(4H, m), 7.23-7.34(2H, m), 7.28(5H, s), 7.51-7.56(2H, m), 7.75(1H, d, J=8.1Hz), 7.83(1H, d, J=8.1Hz), 7.92(2H, d, J=8.2Hz), 7.98(1H, d, J=8.3Hz), 8.63(1H, d, J=8.2Hz), 12.11(1H, s br). 24 97 11.77(s, 1H), 8.67(d, 1H, J=7.9Hz), 8.10-7.99(m, 3H), 6 methyl 7.76(d, 1H, J=8.9Hz), 7.64(d, 1H, J=2.3Hz), ester 7.50-7.44(m, 2H), 7.44-7.36(m, 5H), 7.32-7.16(m, 6H), 5.14(s, 2H), 4.23(t, 2H, J=6.0Hz), 3.99(s, 3H), 3.55(dt, 2H, J=7.6, 6.0Hz). 25 31 ¹H-NMR (DMSO-d₆); δ 12.32(brs, 1H), 8.70(d, 1H, 8 J=8.2Hz), 8.12(d, 1H, J=8.7Hz), 7.99(d, 2H, J=8.6Hz), 7.94(d, 1H, J=8.6Hz), 7.82(d, 1H, J=8.9Hz), 7.64(t, 1H, J=7.3Hz), 7.56(s, 1H), 7.40(d, 1H, J=2.3Hz), 7.32(dd, 1H, J=8.9, 2.3Hz), 7.22-7.16(m, 4H), 4.19(m, 2H), 3.86(m, 4H), 3.25-3.19(m, 6H), 2.23(m, 2H). 25 94 12.01(brs, 1H), 8.93(d, 1H, J=8.6Hz), 8.23-8.01(m, 3H), 6 methyl 7.75(d, 1H, J=8.9Hz), 7.64(d, 1H, J=8.9Hz), 7.60(t, 1H, ester J=7.3Hz), 7.41(d, 1H, J=2.3Hz), 7.17-7.09(m, 6H), 4.16(t, 2H, J=6.9Hz), 3.95(s, 3H), 3.74(t, 4H, J=4.6Hz), 2.58(t, 2H, J=6.9Hz), 2.50(t, 4H, J=4.6Hz), 2.05(tt, 2H, J=6.9, 6.9Hz).  

TABLE 51 26 98 ¹H-NMR (DMSO-d₆); δ 8.79(d, 1H, J=8.3Hz), 8.14(d, 8 1H, J=7.9Hz), 8.07(d, 2H, J=7.9Hz), 7.99(d, 1H, J=8.9Hz), 7.90(d, 1H, J=9.2Hz), 7.74(t, 1H, J=7.6Hz), 7.66(d, 1H, J=2.3Hz), 7.48-7.39(m, 7H), 7.27(d, 4H, J=8.6Hz), 5.11(s, 2H), 4.20(t, 2H, J=5.9Hz), 3.31(q, 2H, J=6.3Hz), 2.08-2.00(m, 2H). 26 66 12.01(brs, 1H), 8.93(dd, 1H, J=8.6, 1.0Hz), 8.10-8.01(m, 6 methyl 3H), 7.75(d, 1H, J=8.9Hz), 7.70-7.57(m, 2H), ester 7.42-7.31(m, 5H), 7.23-7.09(m, 7H), 5.12(s, 2H), 4.13(t, 2H, J=6.3Hz), 3.95(s, 3H), 3.47(q, 2H, J=6.6Hz), 2.09(t, 2H, J=6.6Hz). 27 68 ¹H-NMR (DMSO-d₆); δ 2.14(quint, J=6.6Hz, 2H), 8 2.62(t, J=7.3Hz, 2H), 4.16(t, J=6.3Hz, 2H), 7.11-7.22(m, 5H), 7.30(dd, J=2.6, 8.9Hz, 1H), 7.39(d, J=2.3Hz, 1H), 7.55-7.68(m, 3H), 7.79(d, J=9.2Hz, 1H), 7.89(d, J=8.9Hz, 1H), 7.98(d, J=8.9Hz, 3H), 8.04(dd, J=1.0, 8.3Hz, 1H), 8.49(d, J=8.6Hz, 1H), 8.69(d, J=7.9Hz, 1H), 11.18(s, 1H), 12.15(s, 1H), 13.4-13.8(br, 2H). 27 82 12.01(brs, 1H), 11.16(brs, 1H), 8.92(dd, 1H, J=8.6, 1.0Hz), 6 methyl 8.75(dd, 1H, J=8.6, 1.0Hz), 8.10-8.00(m, 4H), ester 7.74(d, 1H, J=8.9Hz), 7.66-7.52(m, 3H), 7.41(d, 1H, methyl J=2.3Hz), 7.25-7.05(m, 7H), 4.21(t, 2H, J=5.9Hz), ester 3.95(s, 3H), 3.88(s, 3H), 2.73(t, 2H, J=6.9Hz), 2.32(quint, 2H, J=6.3Hz). 28 74 ¹H-NMR (DMSO-d₆); δ 1.93(quint, J=5.9Hz, 2H), 8 3.59(t, J=5.9Hz, 2H), 4.15(t, J=6.3Hz, 2H), 4.58(m, 1H), 7.15-7.21(m, 4H), 7.31(dd, J=2.6, 8.9Hz, 1H), 7.39(d, J=2.0Hz, 1H), 7.56(d, J=2.3Hz, 1H), 7.64(t, J=7.6Hz, 1H), 7.80(d, J=9.2Hz, 1H), 7.91(d, J=9.2Hz, 1H), 7.97(d, J=8.9Hz, 2H), 8.04(dd, J=1.7, 7.9Hz, 1H), 8.69(d, J=7.6, 1H), 12.21(br.s, 1H), 13.79(br.s, 1H). 28 31 12.02(brs, 1H), 8.93(d, 1H, J=7.9Hz), 8.09(dd, 1H, J=7.9, 6 methyl 1.3Hz), 8.04(d, 2H, J=8.6Hz), 7.77(d, 1H, J=8.9Hz), ester 7.67(d, 1H, J=8.2Hz), 7.64-7.59(m, 1H), 7.42(d, 1H, J=2.6Hz), 7.24-7.10(m, 6H), 4.27(t, 2H, J=5.9Hz), 3.96(s, 3H), 3.93(t, 2H, J=5.9Hz), 2.14(quint, 2H, J=5.9Hz).  

TABLE 52 29 21 ¹H-NMR (DMSO-d₆); δ 3.15-3.50(br, 4H), 3.50-3.70(br, 8 2H), 3.80-4.00(br, 4H), 4.50(t-like, 2H), 7.16-7.28(m, 4H), 7.35(dd, J=2.6, 8.9Hz, 1H), 7.48(d, J=2.0Hz, 1H), 7.59(d, J=2.3Hz, 1H), 7.66(t, J=8.9Hz, 1H), 7.86(d, J=9.2Hz, 1H), 7.93(d, J=8.9Hz, 1H), 7.98(d, J=8.9Hz, 2H), 8.05(dd, J=1.7, 7.9Hz, 1H), 8.69(d, J=7.9Hz, 1H),12.14(s, 1H). 29 15 12.02(brs, 1H), 8.93(dd, 1H, J=8.6, 1.0Hz), 8.09(dd, 1H, 6 methyl J=7.9, 1.7Hz), 8.04(d, 2H, J=8.9Hz), 7.76(d, 1H, J=8.9Hz), ester 7.67(d, 1H, J=8.2Hz), 7.64-7.58(m, 1H), 7.42(d, 1H, J=2.3Hz), 7.26-7.09(m, 6H), 4.25(t, 2H, J=5.6Hz), 3.95(s, 3H), 3.79-3.75(m, 4H), 2.89(t, 2H, J=5.6Hz), 2.64(t, 4H, J=4.6Hz). 30 82 ¹H-NMR (DMSO-d₆); δ 1.33-1.52(6H, m), 1.76-1.82(2H, 8 m), 3.37-3.43(2H, m), 4.08(2H, t, J=6.6Hz), 7.15-7.22(4H, m), 7.30(1H, dd, J=8.9, 2.3Hz), 7.37(1H, s), 7.55(1H, d, J=2.3Hz), 7.66(1H, t, J=7.4Hz), 7.80(1H, d, J=9.2Hz), 7.91(1H, d, J=8.9Hz), 7.98(2H, d, J=8.9Hz), 8.05(1H, d, J=8.3Hz), 8.71(1H, d, J=8.6Hz), 12.18(1H, s br). 31 71 ¹H-NMR (DMSO-d₆); δ 12.33(brs, 1H), 8.79(d, 1H, 8 J=8.3Hz), 8.14(dd, 1H, J=7.9, 1.3Hz), 8.07(d, 2H, J=8.9Hz), 7.99(d, 1H, J=9.2Hz), 7.90(d, 1H, J=9.2Hz), 7.74(t, 1H, J=8.6Hz), 7.66(d, 1H, J=2.3Hz), 7.46(d, 1H, J=2.3Hz), 7.41(dd, 1H, J=8.9, 2.3Hz), 7.27(d, 4H, J=8.9Hz), 7.05(t, 1H, J=5.9Hz), 4.18(t, 2H, J=6.6Hz), 3.21(q, 2H, J=6.6Hz), 1.99(t, 2H, J=6.6Hz), 1.47(s, 9H). 31 100 12.02(brs, 1H), 8.93(d, 1H, J=8.9Hz), 8.10-8.07(m, 1H), 6 methyl 8.04(d, 2H, J=8.6Hz), 7.76(d, 1H, J=8.9Hz), 7.67(d, 1H, ester J=9.9Hz), 7.61(t, 1H, J=8.9Hz), 7.42(d, 1H, J=2.3Hz), 7.24-7.10(m, 6H), 4.79(brs, 1H), 4.15(t, 2H, J=6.3Hz), 3.96(s, 3H), 3.39(q, 2H, J=6.3Hz), 2.10-2.05(m, 2H), 1.46(s, 9H). 32 91 ¹H-NMR (DMSO-d₆); δ 1.40-1.53(m, 2H), 1.53-1.65(m, 8 2H), 1.78(quint, J=6.3Hz, 2H), 2.25(t, J=7.3Hz, 2H), 4.07(t, J=6.3Hz, 2H), 7.15-7.22(m, 4H), 7.30(dd, J=2.3, 8.9Hz, 1H), 7.38(d, J=2.3Hz, 1H), 7.56(d, J=2.3Hz, 1H), 7.65(t, J=8.6Hz, 1H), 7.79(d, J=9.2Hz, 1H), 7.90(d, J=8.9Hz, 1H), 7.97(d, J=8.9Hz, 2H), 8.04(dd, J=1.7, 7.9Hz, 1H), 8.69(d, J=8.6Hz, 1H), 12.05(br.s, 1H), 12.17(s, 1H).  

TABLE 53 32 67 12.02(brs, 1H), 8.93(d, 1H, J=8.3Hz), 8.09(dd, 1H, J=8.3, 6 methyl 1.7Hz), 8.04(d, 2H, J=8.6Hz), 7.76(d, 1H, J=8.9Hz), ester 7.68-7.58(m, 2H), 7.42(d, 1H, J=2.3Hz), 7.25-7.10(m, ethyl 6H), 4.14(q, 2H, J=7.3Hz), 4.09(t, 2H, J=7.3Hz), 3.95(s, ester 3H), 2.37(t, 2H, J=7.3Hz), 1.89(quint, 2H, J=7.3Hz), 1.75(quint, 2H, J=7.3Hz), 1.62-1.51(m, 2H), 1.27(t, 3H, J=7.3Hz). 33 33 ¹H-NMR (DMSO-d₆); δ 2.07(quint, J=5.9Hz, 2H), 37 2.95-3.10(m, 2H), 4.18(t, J=5.9, 2H), 7.15-7.23(m, 4H), 7.33(dd, J=2.3, 8.9Hz, 1H), 7.38(d, J=2.0Hz, 1H), 7.57(d, J=2.6Hz, 1H), 7.61-7.64(m, 1H), 7.82(d, J=8.9Hz, 1H), 7.91(d, J=9.2Hz, 1H), 7.98(d, J=8.9Hz, 2H), 8.04(d, J=8.3Hz, 1H), 8.69(d, J=8.6Hz, 1H). 34 58 ¹H-NMR (DMSO-d₆); δ 1.13(t, 3H, J=6.92Hz), 3.50(q, 11 2H, J=6.93Hz), 3.69(t, 2H, J=4.62Hz), 3.72(s, 2H), 4.06(t, 2H, J=4.62Hz), 6.91(d, 2H, J=8.59Hz), 6.97(s, 4H), 7.13(ddd, 1H, J=1.32, 7.59, 7.92Hz), 7.32(d, 2H, J=8.58Hz), 7.57(ddd, 1H, J=1.65, 6.93, 8.58Hz), 7.95(dd, 1H, J=1.32, 7.91Hz), 8.50(d, 1H, J=8.25Hz), 11.13(s, 1H), 13.56(br, 1H). 34 103 11.04(brs, 1H), 8.71(d, 1H, J=8.58Hz), 7.98(dd, 1H, 10 methyl J=7.91, 1.65Hz), 7.50(ddd, 1H, J=8.58, 7.26, 1.65Hz), ester 7.30(d, 2H, J=8.58Hz), 7.05(ddd, 1H, J=7.92, 7.26, 0.99Hz), 7.00-6.87(m, 6H), 4.09(t, 2H, J=4.62Hz), 3.86(s, 3H), 3.77(t, 2H, J=4.62Hz), 3.71(s, 2H), 3.60(q, 2H, J=6.91Hz), 1.24(t, 3H, J=6.91Hz). 35 58 ¹H-NMR (DMSO-d₆); δ 3.39(s, 3H), 3.72(s, 2H), 5.16(s, 8 2H, 6.92(d, J=8.6Hz, 2H), 6.99(d, J=9.2Hz, 2H), 7.04(d, J=9.2Hz, 2H), 7.13(dd, J=6.9, 7.9Hz, 1H), 7.33(d, J=8.6Hz, 2H), 7.57(ddd, J=1.7, 6.9, 8.6Hz, 1H), 7.95(dd, J=1.7, 7.9Hz, 1H), 8.50(d, J=8.6Hz, 1H), 11.17(s, 1H). 35 86 11.04(brs, 1H), 8.72(dd, 1H, J=8.6Hz, 1.0Hz), 7.98(dd, 6 methyl 1H, J=8.2, 1.7Hz), 7.51(ddd, 1H, J=8.6, 6.9, 1.7Hz), ester 7.31(d, 2H, J=8.6Hz), 7.04(ddd, 1H, J=8.2, 6.9, 1.0Hz), 7.00(d, 2H, J=6.3Hz), 6.98(d, 2H, J=6.3Hz), 6.97(d, 2H, J=8.6Hz), 5.13(s, 2H), 3.86(s, 3H), 3.72(s, 2H), 3.48(s, 3H).  

TABLE 54 36  39 1.91-2.13(m, 4H), 2.76(s, 3H), 2.94-3.33(m, 4H), 3.73(s, 11 2H), 4.62(br, 1H), 6.93(d, J=8.6Hz, 2H), 6.99(d, J=9.2Hz, 2H), 7.04(d, J=9.2Hz, 2H), 7.13(dd, J=6.9, 8.3Hz, 1H), 7.34(d, J=8.6Hz, 2H), 7.56(ddd, J=1.3, 6.9, 8.3Hz, 1H), 7.95(dd, J=1.3, 8.3Hz, 1H), 8.50(d, J=8.3Hz, 1H). 36 100 11.04(brs, 1H), 8.72(d, 1H, J=8.6Hz), 7.99(dd, 1H, J=7.9Hz, 10 methyl 1.7Hz), 7.52(ddd, 1H, J=8.6, 7.3, 1.7Hz), 7.31(d, 2H, ester J=8.6Hz), 7.06(dd, 1H, J=7.9, 7.3Hz), 6.97(d, 2H, J=9.2Hz), 6.96(d, 2H, J=8.6Hz), 6.87(d, 2H, J=9.2Hz), 4.16-4.26(m, 1H), 3.87(s, 3H), 3.72(s, 2H), 2.54-2.70(m, 2H), 2.30(s, 3H), 1.96-2.03(m, 2H), 1.77-1.90(m, 2H), 1.23-1.30(m, 2H). 37  58 ¹H-NMR (DMSO-d₆); δ 3.71(s, 2H), 5.16(s, 2H), 6.90(d, 11 yield 2H, J=8.24Hz), 7.02(d, 2H, J=4.95Hz), 7.02(d, 2H, from J=4.95Hz), 7.11(dd, 1H, J=6.93, 7.92Hz), 7.32(d, 2H, Ex. 6 J=8.56Hz), 7.43(d, 2H, J=5.61Hz), 7.56(dd, 1H, J=6.93, 8.58Hz), 7.94(d, 1H, J=7.59Hz), 8.49(d, 1H, J=8.25Hz), 8.57(d, 2H, J=5.93Hz), 11.17(br, 1H). 37 100 11.07(br, 1H), 8.73(d, 1H, J=8.58Hz), 8.58(d, 2H, J=5.94Hz), 10 methyl 7.97(dd, 1H, J=8.24, 1.65Hz), 7.71-7.30(m, 5H), ester 7.05-6.89(m, 7H), 5.03(s, 2H), 3.83(s, 3H), 3.71(s, 2H). 38  50 ¹H-NMR (DMSO-d₆); δ 3.34(br, 4H), 3.53(t, 2H, J=4.95Hz), 11 3.72(s, 2H), 3.87(br, 4H), 4.37(t, 2H, J=4.95Hz), 6.91(d, 2H, J=8.58Hz), 7.03(s, 4H), 7.13(ddd, 1H, J=1.32, 7.26, 7.59Hz), 7.33(d, 2H, J=8.91Hz), 7.57(ddd, 1H, J=1.32, 7.26, 8.58Hz), 7.95(dd, 1H, J=1.65, 7.91Hz), 8.49(d, 1H, J=7.59Hz), 11.11(s, 1H). 38  72 11.04(brs, 1H), 8.72(d, 1H, J=8.58Hz), 7.99(dd, 1H, 10 methyl J=7.91, 1.32Hz), 7.51(ddd, 1H, J=8.58, 7.25, 1.32Hz), ester 7.31(d, 2H, J=8.58Hz), 7.05(dd, 1H, J=7.91, 7.59Hz), 7.00-6.85(m, 6H), 4.08(t, 2H, J=5.94Hz), 3.87(s, 3H), 3.73(t, 4H, J=4.52Hz), 3.72(s, 2H), 2.79(t, 2H, J=5.94Hz), 2.58(t, 4H, J=4.62Hz). 39  40 ¹H-NMR (DMSO-d₆); δ 2.16(br, 4H), 3.41(br, 4H), 11 3.65(t, 2H, J=4.62Hz), 3.82(s, 2H), 4.40(t, 2H, J=4.97Hz), 7.01(d, 2H, J=8.58Hz), 7.12(s, 4H), 7.22(dd, 1H, J=7.26, 8.54Hz), 7.43(d, 2H, J=8.58Hz), 7.66(dd, 1H, J=7.26, 8.24Hz), 8.04(d, 1H, J=7.92Hz), 8.58(d, 1H, J=8.25Hz), 11.26(s, 1H).  

TABLE 55 39 63 11.03(brs, 1H), 8..71(dd, 1H, J=8.58, 0.99Hz), 7.99(dd, 10 methyl 1H, J=8.25, 1.65Hz), 7.52(m, 1H), 7.31(d, 2H, J=8.59Hz), ester 7.06(m, 1H), 7.01-6.85(m, 6H), 4.09(t, 2H, J=5.94Hz), 3.87(s, 3H), 3.72(s, 2H), 2.91(t, 2H, J=5.94Hz), 2.65(br, 4H), 1.82(t, 4H, J=3.63Hz). 40 50 ¹H-NMR (DMSO-d₆); δ 1.39-1.41(m, 2H), 1.51-1.55(m, 11 4H), 2.50-2.53(m, 4H), 2.74(t, J=5.9Hz, 2H), 3.56(s, 2H), 4.07(t, J=5.9Hz, 2H), 6.86(d, J=8.6Hz, 2H), 6.91-6.97(m, 5H), 7.24-7.28(m, 1H), 7.30(d, J=8.6Hz, 2H), 8.00(dd, J=1.7, 7.6Hz, 1H), 8.42(d, J=8.3Hz, 1H), 11.20(s, 1H). 40 69 11.04(brs, 1H), 8.72(d, 1H, J=8.3Hz), 7.98(dd, 1H, J=8.3Hz), 10 methyl 1.3Hz), 7.51(ddd, 1H, J=8.3, 7.3, 1.3Hz), 7.30(d, 2H, ester J=8.6Hz), 7.05(dd, 1H, J=8.3, 7.3Hz), 6.97(d, 2H, J=9.2Hz), 6.95(d, 2H, J=8.6Hz), 6.87(d, 2H, J=9.2Hz), 4.08(t, 2H, J=6.3Hz), 3.87(s, 3H), 3.72(s, 2H), 2.76(t, 2H, J=6.3Hz), 2.51-2.52(m, 4H), 1.54-1.64(m, 6H). 41 15 ¹H-NMR (DMSO-d₆); δ 2.82(s, 3H), 3.50(br, 10H), 8 3.73(s, 2H), 4.33(br, 2H), 6.91(d, J=8.6Hz, 2H), 7.03(s, 4H), 7.14(dd, J=7.3, 7.9Hz, 1H), 7.34(d, J=8.6Hz, 2H), 7.57(dd, J=7.3, 8.6Hz, 1H), 7.95(d, J=7.9Hz, 1H), 8.50(d, J=8.6Hz, 1H), 11.12(s, 1H). 41 38 11.04(brs, 1H), 8.71(dd, 1H, J=8.6, 0.7Hz), 7.99(dd, 1H, 6 methyl J=7.9, 1.7Hz), 7.52(ddd, 1H, J=8.6, 8.3, 1.7Hz), 7.31(d, ester 2H, J=8.9Hz), 7.07(dd, 1H, J=8.3, 7.9, 0.7Hz), 6.98(d, 2H, J=7.3Hz), 6.95(d, 2H, J=7.3Hz), 6.86(d, 2H, J=8.9Hz), 4.08(t, 2H, J=5.9Hz), 3.88(S, 3H), 3.72(S, 2H), 2.82(t, 2H, J=5.9Hz), 2.64(br, 4H), 2.51(br, 4H), 2.31(s, 3H). 42 ¹H-NMR (DMSO-d₆); δ 1.43-1.56(m, 6H), 3.40(brm, 30 4H), 3.57(s, 2H), 4.76(s, 2H), 6.86-6.99(m, 7H), 7.24-7.32(m, 3H), 8.00(dd, J=1.7, 7.6Hz, 1H), 8.42(d, J=7.9Hz, 1H), 14.13(brs, 1H). 42 67 11.04(brs, 1H), 8.71(dd, 1H, J=8.6, 1.0Hz), 7.99(dd, 1H, 29 methyl J=7.9, 1.7Hz), 7.52(ddd, 1H, J=8.6, 7.3, 1.7Hz), 7.31(dd, ester 2H, J=8.6, 2.0Hz), 7.06(ddd, 1H, J=7.9, 7.3, 1.0Hz), 6.98(d, 2H, J=9.2, 2.6Hz), 6.96(dd, 2H, J=9.2, 2.6Hz), 6.92(d, 2H, J=8.6, 2.0Hz), 4.66(s, 2H), 3.87(S, 3H), 3.72(S, 2H), 3.55-3.58(br, 2H), 3.46-3.50(br, 2H), 1.57-1.68(br, 6H).  

TABLE 56 43 37 ¹H-NMR (DMSO-d₆); δ 3.72(2H, s), 4.30(4H, s), 11 6.91(2H, d, J=8.6Hz), 6.92-7.01(8H, m), 7.12(1H, dd, J=7.9, 7.3Hz), 7.30(1H, t, J=7.3Hz), 7.32(2H, d, J=8.6Hz), 7.56(1H, ddd, J=8.6, 7.3, 1.7Hz), 7.95(1H, dd, J=7.9, 1.7Hz), 8.50(1H, d, J=8.6Hz), 11.24(1H, brs), 13.50-13.60(1H, br). 43 68 11.04(brs, 1H), 8.71(dd, 1H, J=8.6, 1.0Hz), 7.99(dd, 1H, 10 methyl J=8.2, 1.7Hz), 7.52(ddd, 1H, J=8.6, 7.3, 1.7Hz), ester 7.25-7.33(m, 4H), 7.06(ddd, 1H, J=8.2, 7.3, 1.0Hz), 6.90-7.02(m, 9H), 4.31(s, 4H), 3.87(S, 3H), 3.72(S, 2H). 44 44 ¹H-NMR (DMSO-d₆); δ 1.59(m, 2H), 1.92(m, 2H), 11 Yield 3.46(m, 2H), 3.58(s, 2H), 3.86(m, 2H), 4.48(m, 1H), from 6.88(d, 2H, J=8.58Hz), 6.92(m, 1H), 6.95(s, 4H), 7.26(m, Ex. 6 1H), 7.30(d, 2H, J=8.25Hz), 8.01(dd, 1H, J=1.65, 7.92Hz), 8.43(d, 1H, J=8.24Hz), 13.84(br, 1H). 44 — 11.04(brs, 1H), 8.70(d, 1H, J=8.58Hz), 7.99(dd, 1H, 10 methyl J=7.91, 1.65Hz), 7.52(ddd, 1H, J=8.57, 7.26, 1.65Hz), ester 7.31(d, 2H, J=8.25Hz), 7.06(ddd, 1H, J=8.25, 7.25, 0.99Hz), 6.99-6.91(m, 4H), 6.88(d, 2H, J=9.24Hz), 4.40(quint, 1H, J=3.96Hz), 3.97(m, 2H), 3.87(s, 3H), 3.72(s, 2H), 3.56(m, 2H), 2.06-1.96(m, 2H), 1.84-1.72(m, 2H). 45 70 ¹H-NMR (DMSO-d₆); δ 11.15(brs, 1H), 9.85(s, 1H), 11 8.50(d, 1H, J=8.57Hz), 7.79(dd, 1H, J=7.91, 1.48Hz), 7.56(dd, 1H, J=7.09, 6.76Hz), 7.49(d, 2H, J=8.24Hz), 7.31(d, 2H, J=8.57Hz), 7.22(d, 2H, J=8.24Hz), 7.12(dd, 1H, J=8.08, 7.09Hz), 6.95(s, 4H), 6.89(d, 2H, J=8.57Hz), 4.12(t, 2H, J=6.76Hz), 3.71(s, 2H), 2.96(t, 2H, J=6.76Hz), 2.01(s, 3H). 45 79 11.03(brs, 1H), 8.69(dd, 1H, J=8.64, 1.08Hz), 7.97(dd, 10 methyl 1H, J=8.10, 1.62Hz), 7.67-7.42(m, 4H), 7.29(d, 2H, ester J=8.64Hz), 7.21(d, 2H, J=8.37Hz), 7.05(ddd, 1H, J=8.10, 7.29, 1.08Hz), 6.97-6.80(m, 5H), 4.10(t, 2H, J=7.02Hz), 3.86(s, 3H), 3.71(s, 2H), 3.03(t, 2H, J=7.02Hz), 2.14(s, 3H). 47 55 ¹H-NMR (DMSO-d₆) δ 2.61(s, 6H), 3.15(t, 2H, J=4.95Hz), 11 Yield 3.60(s, 2H), 4.20(t, 2H, J=5.28Hz), 6.87(d, 2H, from J=7.92Hz), 6.98-7.02(m, 5H), 7.28-7.39(m, 3H), 7.95(d, Ex 6 1H, J=6.92Hz), 8.44(d, 1H, J=8.25Hz), 13.11(br, 1H).  

TABLE 57 47 — 11.03(br, 1H), 8.71(dd, 1H, J=8.58, 0.99Hz), 7.98(dd, 1H, 10 methyl J=8.24, 1.65Hz), 7.51(ddd, 1H, J=8.58, 7.25, 1.65Hz), ester 7.31(d, 2H, J=8.58Hz), 7.05(ddd, 1H, J=8.24, 7.26, 0.99Hz), 7.01-6.86(m, 6H), 4.04(t, 2H, J=5.61Hz), 3.87(s, 3H), 3.72(s, 2H), 2.73(t, 2H, J=5.61Hz), 2.34(s, 6H). 89  32 ¹H-NMR (DMSO-d₆); δ 3.35(s, 6H), 4.12(t, 2H, J=4.29Hz), 11 4.54(t, 2H, J=4.62Hz), 7.09-7.25(m, 7H), 7.68(dd, 1H, J=7.25, 7.53Hz), 7.98(d, 2H, J=8.56Hz), 8.08(d, 1H, J=7.91Hz), 8.71(d, 1H, J=8.26Hz), 12.20(s, 1H). 89 105 11.98(brs, 1H), 8.91(d, 1H, J=8.57Hz), 8.06(dd, 1H, 10 methyl J=7.92, 1.65Hz), 8.00(d, 2H, J=8.57Hz), 7.59(ddd, 1H, ester J=8.58, 7.26, 1.65Hz), 7.09(dd, 1H, J=7.59, 7.58Hz), 7.03-6.92(m, 6H), 4.07(t, 2H, J=5.61Hz), 3.94(s, 3H), 2.75(t, 2H, J=5.61Hz), 2.36(s, 6H). 90  54 ¹H-NMR (DMSO-d₆); δ 12.37(s, 1H), 8.78(d, 1H, J=8.58Hz), 11 8.14(d, 1H, J=7.91Hz), 8.04(d, 2H, J=8.58Hz), 7.73(dd, 1H, J=8.58, 6.93Hz), 7.28(dd, 1H, J=7.92, 7.59Hz), 7.23-7.14(m, 6H), 4.36(t, 2H, J=4.95Hz), 3.84(t, 4H, J=4.95Hz), 3.26(br, 2H), 3.04(br, 4H). 90  83 11.98(s, 1H), 8.92(d, 1H, J=8.24Hz), 8.06(dd, 1H, 10 methyl J=7.91, 1.32Hz), 8.00(d, 2H, J=8.56Hz), 7.59(ddd, 1H, ester J=8.58, 7.26, 1.32Hz), 7.10(dd, 1H, J=7.92, 7.25Hz), 7.04-6.91(m, 6H), 4.11(t, 2H, J=5.62Hz), 3.94(s, 3H), 3.75(t, 4H, J=4.62Hz), 2.82(t, 2H, J=5.62Hz), 2.59(t, 4H, J=4.62Hz). 91  13 ¹H-NMR (DMSO-d₆); δ 3.20-3.90(br, 10H), 4.48(s, 2H), 11 yield 7.15-7.32(m, 7H), 7.74(t, 1H, J=7.26Hz), 8.04(d, 2H, from J=8.91Hz), 8.14(dd, 1H, J=1.32, 7.92Hz), 8.78(d, 1H, Ex. 6 J=7.92Hz), 9.61(br, 1H), 12.19(s, 1H). 92  50 ¹H-NMR (DMSO-d₆); δ 1.96(br, 4H), 2.80-3.80(br, 4H), 11 3.58(t, 2H, J=4.94Hz), 4.35(t, 2H, J=4.94Hz), 7.06-7.21(m, 7H), 7.64(ddd, 1H, J=1.65, 7.26, 8.24Hz), 7.95(d, 2H, J=8.90Hz), 8.05(dd, 1H, J=1.65, 8.25Hz), 8.69(d, 1H, J=7.92Hz), 10.55(br, 1H), 12.24(s, 1H).  

TABLE 58  92 54 11.98(brs, 1H), 8.92(d, 1H, J=8.26Hz), 8.06(dd, 1H, 10 methyl J=7.91, 1.32Hz), 8.00(d, 1H, J=8.91Hz), 7.58(dd, 1H, ester J=7.26, 6.93Hz), 7.09(dd, 1H, J=7.91, 7.59Hz), 7.04-6.92(m, 6H), 4.11(t, 2H, J=5.94Hz), 3.94(s, 3H), 2.91(t, 2H, J=5.94Hz), 2.64(brm, 4H), 1.82(brm, 4H).  93 31 ¹H-NMR (DMSO-d₆); δ 1.42-1.83(br, 6H), 3.03(br, 2H), 11 3.33(br, 2H), 3.48(br, 2H), 4.42(t, J=5.0Hz, 2H), 7.08(d, J=8.6Hz, 2H), 7.09(d, J=8.9Hz, 2H), 7.14(d, J=8.9Hz, 2H), 7.19(dd, J=7.6, 8.6Hz, 1H), 7.65(ddd, J=1.3, 7.6, 7.9Hz), 1H), 7.95(d, J=8.6Hz, 2H), 8.06(dd, J=1.3, 7.9Hz, 1H), 8.70(d, J=8.6Hz, 1H), 10.37(br, 1H), 12.15(s, 1H), 13.76(br, 1H).  93 100 11.98(s, 1H), 8.92(d, 1H, J=8.6Hz), 8.06(dd, 1H, J=8.2, 10 methyl 1.7Hz), 8.00(d, 2H, J=8.9Hz), 7.58(ddd, 1H, J=8.6, 7.3, ester 1.7Hz), 7.09(dd, 1H, J=8.2, 7.3Hz), 6.99-7.03(m, 4H), 6.93(d, 2H, J=9.2Hz), 4.10(t, 2H, J=5.9Hz), 3.94(S, 3H), 2.78(t, 2H, J=5.9Hz), 2.50-2.54(m, 4H), 1.54-1.64(m, 4H), 1.42-1.52(m, 2H).  94 100 ¹H-NMR (DMSO-d₆); δ 2.83(s, 3H), 3.46(br, 12H), 8 4.37(br, 2H), 7.06-7.14(m, 6H), 7.19(dd, J=7.9, 8.6Hz, 1H), 7.66(dd, J=7.3, 8.6Hz, 1H), 7.95(d, J=8.9Hz, 2H), 8.06(dd, J=1.7, 7.9Hz, 1H), 8.70(d, J=7.3Hz, 1H), 12.12(s, 1H).  94 54 11.98(brs, 1H), 8.91(d, 1H, J=8.2Hz), 8.06(dd, 1H, J=8.2, 6 methyl 1.7Hz), 8.00(d, 2H, J=8.9Hz), 7.59(ddd, 1H, J=8.2, 7.3, ester 1.7Hz), 7.10(dd, 1H, J=8.2, 7.3Hz), 7.00-7.03(m, 4H), 6.93(d, 2H, J=9.2Hz), 4.11(t, 2H, J=5.9Hz), 3.94(S, 3H), 2.84(t, 2H, J=5.9Hz), 2.65(br, 4H), 2.52,(br, 4H), 2.32(s, 3H). 121 98 ¹H-NMR (DMSO-d₆); δ 11.20(s, 1H), 8.57(d, 1H, J=8.4Hz), 21 7.99(d, 1H, J=7.6Hz), 7.87-7.90(m, 2H), 7.75(d, 1H, J=6.8Hz), 7.54-7.65(m, 4H), 7.35(d, 2H, J=8.4Hz), 7.13(t, 1H, J=7.6Hz), 6.92-6.99(m, 6H), 4.33(brs, 1H), 3.74(s, 2H), 3.14(br, 1H), 1.71-1.82(brm, 2H), 1.45-1.61(brm, 6H). 121 60 11.04(brs, 1H), 8.71(d, 1H, J=7.3Hz), 8.00(dd, 1H, J=7.8, 21 methyl 1.4Hz), 7.90(dd, 2H, J=8.1, 1.4Hz), 7.49-7.58(m, 4H), ester 7.23-7.32(m, 3H), 7.07(ddd, 1H, J=8.1, 7.3, 1.4Hz), 6.93-6.96(m, 4H), 6.80-6.87(d, 2H, J=9.2Hz), 4.47(d, 1H, J=7.6Hz), 4.31(br, 1H), 3.88(s, 3H), 3.72(s, 2H), 3.31(brm, 1H), 1.90-1.93(m, 2H), 1.58-1.66(m, 6H).  

TABLE 59 124 93 ¹H-NMR (DMSO-d₆); δ 11.20(s, 1H), 8.56(d, 1H, J=8.4Hz), 21 8.04(d, 1H, J=0.8Hz), 7.96-7.99(m, 2H), 7.80-7.85(m, 2H), 7.56(dd, 1H, J=7.8, 7.6Hz), 7.34(d, 2H, J=8.4Hz), 7.13(dd, 1H, J=8.4, 7.6Hz), 6.92-6.99(m, 6H), 4.36(brs, 1H), 3.74(s, 2H), 3.20(br, 1H), 1.80-1.84(brm, 2H), 1.50-1.60(brm, 6H). 124 44 11.05(brs, 1H), 8.71(d, 1H, J=8.4Hz), 7.96-8.01(m, 2H), methyl 7.71(dd, 1H, J=8.4, 1.9Hz), 7.59(d, 1H, J=8.4Hz), ester 7.52(ddd, 1H, J=8.4, 7.3, 1.9Hz), 7.30(d, 2H, J=8.4Hz), 7.07(ddd, 1H, J=7.8, 7.3, 1.1Hz), 6.94-6.97(m, 4H), 6.82(d, 2H, J=9.2Hz), 4.61(d, 1H, J=7.8Hz), 4.34(br, 1H), 3.88(s, 3H), 3.72(s, 2H), 3.29(brm, 1H), 1.94-1.98(m, 2H), 1.58-1.69(m, 6H). 207 82 ¹H-NMR (DMSO-d₆); δ 13.56(br, 1H), 11.13(s, 1H), 21 8.51(d, 1H, J=8.4Hz), 7.95(dd, 1H, J=7.8, 1.6Hz), 7.86(d, 1H, J=7.3Hz), 7.47-7.71(m, 5H), 7.33(dd, 2H, J=8.4Hz), 7.13(dd, 1H, J=7.8, 7.3Hz), 6.90-6.97(m, 6H), 4.35(brs, 1H), 3.72(s, 2H), 3.16(br, 1H), 1.78(brm, 2H), 1.45-1.58(brm, 6H). 207 77 11.05(brs, 1H), 8.71(d, 1H, J=8.4Hz), 7.99(dd, 1H, J=8.1, 21 methyl 1.6Hz), 7.70(d, 1H, J=7.8Hz), 7.46-7.63(m, 3H), ester 7.24-7.32(m, 4H), 7.07(dd, 1H, J=8.1, 7.3Hz), 6.93-6.97(m, 4H), 6.82(d, 2H, J=9.2Hz), 4.32(br, 1H), 3.87(s, 3H), 3.72(s, 2H), 3.28-3.36(m, 1H), 1.93-1.96(m, 2H), 1.55-1.68(m, 6H). 214 77 ¹H-NMR (DMSO-d₆); δ 13.54(br, 1H), 11.13(s, 1H), 21 8.51(d, 1H, J=8.4Hz), 7.94-8.07(m, 6H), 7.57(ddd, 1H, J=8.4, 7.3, 1.4Hz), 7.32(d, 2H, J=8.4Hz), 7.13(dd, 1H, J=7.8, 7.3Hz), 6.90-6.98(m, 6H), 4.35(brs, 1H), 3.73(s, 2H), 3.18(br, 1H), 1.79-1.80(brm, 2H), 1.46-1.59(m, 6H). 214 90 11.05(s, 1H), 8.71(dd, 1H, J=8.4, 0.8Hz), 8.03(d, 2H, 21 methyl J=8.4Hz), 7.99(d, 1H, J=8.1, 1.4Hz), 7.77(d, 2H, J=8.4Hz), ester 7.52(ddd, 1H, J=8.4, 7.3, 1.4Hz), 7.31(d, 2H, J=8.9Hz), 7.07(ddd, 1H, J=8.1, 7.3, 0.8Hz), 6.91-7.04(m, 4H), 6.81(d, 2H, J=6.8Hz), 4.93(d, 1H, J=7.6Hz), 4.32(br, 1H), 3.87(s, 3H), 3.73(s, 2H), 3.27-3.33(m, 1H), 1.93-1.97(m, 2H), 1.57-1.69(m, 6H).  

TABLE 60 215 80 ¹H-NMR (DMSO-d₆); δ 8.49(d, 1H, J=8.1Hz), 7.97(s, 21 1H), 7.96(d, 2H, J=8.6Hz), 7.87(d, 1H, J=7.0Hz), 7.58(d, 2H, J=8.6Hz), 7.51-7.57(m, 1H), 7.32(d, 2H, J=8.6Hz), 7.11(dd, 1H, J=8.1, 7.3Hz), 6.89-6.97(m, 6H), 4.34(br, 1H), 3.70(s, 2H), 3.15(br, 1H), 1.79(brm, 2H), 1.45-1.58(m, 6H). 215 93 11.05(s, 1H), 8.71(d, 1H, J=8.4Hz), 8.11(d, 1H, J=7.0Hz), 21 methyl 7.95-8.01(m, 3H), 7.51(ddd, 1H, J=8.4, 7.3, 1.6Hz), ester 7.43(d, 1H, J=8.6Hz), 7.32(d, 2H, J=8.9Hz), 7.31(d, 2H, J=8.4Hz), 7.06(dd, 1H, J=7.3, 7.0Hz), 6.88-6.93(m, 4H), 6.81(d, 2H, J=8.9Hz), 5.21(d, 1H, J=7.6Hz), 4.31(br, 1H), 3.86(s, 3H), 3.73(s, 2H), 3.27-3.33(m, 1H), 1.92-1.97(m, 2H), 1.57-1.71(m, 6H). 217 88 11.05(brs, 1H), 8.70(dd, 1H, J=8.3, 0.9Hz), 8.21(t, 1H, 21 methyl J=1.4Hz), 8.13(ddd, 1H, J=7.8, 1.6, 1.4Hz), 7.99(dd, 1H, ester J=8.1, 1.6Hz), 7.83(ddd, 1H, J=8.1, 1.6, 1.4Hz), 7.64(dd, 1H, J=8.1, 7.8Hz), 7.51(ddd, 1H, J=8.3, 7.3, 1.6Hz), 7.31(d, 2H, J=8.3Hz), 7.06(ddd, 1H, J=8.1, 7.3, 0.9Hz), 6.92-6.97(m, 4H), 6.81(d, 2H, J=7.0Hz), 5.32(d, 1H, J=7.6Hz), 4.32(brs, 1H), 3.87(s, 3H), 3.73(s, 2H), 3.26-3.39(m, 1H), 1.93-1.98(m, 1H), 1.57-1.67(m, 6H). 410 37 ¹H-NMR (DMSO-d₆); δ 11.13(s, 1H), 8.45(d, 1H, J=8.57Hz), 11 8.08(s, 1H), 7.96(d, 1H, J=7.92Hz), 7.81(d, 1H, J=8.25Hz), 7.57(dd, 1H, J=7.59, 7.92Hz), 7.18-7.03(m, 5H), 6.97(d, 1H, J=8.25Hz), 4.39-4.37(m, 2H), 4.00-3.70(brm, 4H), 3.80-3.77(m, 2H), 3.60-3.49(m, 2H), 3.32(br, 4H). 410 44 11.17(brs, 1H), 8.68(d, 1H, J=8.58Hz), 8.16(d, 1H, 10 methyl J=2.31Hz), 8.01(dd, 1H, J=1.32, 7.92Hz), 7.71(dd, 1H, ester J=2.31, 8.58Hz), 7.53(ddd, 1H, J=1.32, 7.26, 8.58Hz), 7.11-7.05(m, 3H), 6.93-6.87(m, 3H), 4.12(t, 2H, J=5.61Hz), 3.89(s, 3H), 3.76-3.73(m, 4H), 3.70(s, 2H), 2.82(t, 2H, J=5.61Hz), 2.61-2.58(m, 4H). 411 45 ¹H-NMR (DMSO-d₆); δ 14.13(br, 1H), 8.41(d, 1H, 11 J=8.25Hz), 8.06(d, 1H, J=2.31Hz), 8.00(dd, 1H, J=1.65, 7.92Hz), 7.79(dd, 1H, J=2.31, 8.58Hz), 7.70(d, 1H, J=1.65Hz), 7.28(ddd, 1H, J=1.65, 7.26, 8.25Hz), 7.04(s, 4H), 6.98-6.92(m, 2H), 6.59(d, 1H, J=3.30Hz), 6.48(dd, 1H, J=1.98, 2.97Hz), 5.05(s, 2H), 3.62(s, 2H).  

TABLE 61 411 50 11.17(brs, 1H), 8.68(d, 1H, J=8.25Hz), 8.16(d, 1H, 10 methyl J=1.98Hz), 8.00(dd, 1H, J=1.32, 7.92Hz), 7.72(dd, 1H, ester J=2.31, 8.58Hz), 7.53(ddd, 1H, J=1.65, 7.25, 8.58Hz), 7.45(dd, 1H, J=0.99, 1.98Hz), 7.13-6.97(m, 5H), 6.88(d, 1H, J=8.58Hz), 6.43(d, 1H, J=2.97Hz), 6.38(dd, 1H, J=1.98, 2.97Hz), 4.99(s, 2H), 3.89(s, 3H), 3.70(s, 2H). 412 15 ¹H-NMR (DMSO-d₆); δ 11.32(brs, 1H), 8.69(brs, 1H), 11 8.56(brs, 1H), 8.45(d, 1H, J=8.25Hz), 8.09(s, 1H), 7.96(d, 1H, J=7.92Hz), 7.89(d, 1H, J=7.92Hz), 7.81(d, 1H, J=8.58Hz), 7.63-7.52(m, 2H), 7.44(dd, 1H, J=7.25, 7.59Hz), 7.16-7.07(m, 5H), 6.96(d, 1H, J=8.58Hz), 5.16(s, 2H), 3.76(s, 2H). 413 35 ¹H-NMR (DMSO-d₆); δ 14.00-13.00(br, 1H), 11 11.90-11.30(br, 1H), 11.12(brs, 1H), 8.45(d, 1H, J=8.25Hz), 8.08(s, 1H), 7.95(d, 1H, J=7.92Hz), 7.81(d, 1H, J=8.25Hz), 7.58(dd, 1H, J=7.59, 7.92Hz), 7.18-6.96(m, 6H), 4.39(s, 2H), 3.77-3.44(br, 12H), 2.83(s, 3H). 413 72 11.17(brs, 1H), 8.68(d, 1H, J=8.58Hz), 8.16(d, 1H, 10 methyl J=2.64Hz), 8.01(dd, 1H, J=1.65, 7.92Hz), 7.71(dd, 1H, ester J=2.64, 8.58Hz), 7.53(ddd, 1H, J=1.65, 7.26, 8.57Hz), 7.11-7.04(m, 3H), 6.94-6.86(m, 3H), 4.10(t, 2H, J=5.61Hz), 3.89(s, 3H), 3.70(s, 2H), 2.82(t, 2H, J=5.61Hz), 2.63(br, 4H), 2.49(br, 4H), 2.30(s, 3H). 414 56 ¹H-NMR (DMSO-d₆); δ 13.90-13.30(br, 1H), 11.16(s, 11 1H), 10.12-9.71(br, 1H), 8.45(d, 1H, J=8.25Hz), 8.08(d, 1H, J=2.31Hz), 7.96(d, 1H, J=7.92Hz), 7.82(dd, 1H, J=2.31, 8.25Hz), 7.57(dd, 1H, J=7.26, 8.58Hz), 7.17-6.96(m, 6H), 4.38(brt, 2H, J=4.95Hz), 3.77(s, 2H), 3.58-3.38(brm, 4H), 3.15-2.86(m, 2H), 1.87-1.28(m, 6H). 414 72 11.16(brs, 1H), 8.68(d, 1H, J=8.58Hz), 8.16(d, 1H, 10 methyl J=2.64Hz), 8.00(dd, 1H, J=1.65, 7.92Hz), 7.71(dd, 1H, ester J=2.64, 8.58Hz), 7.52(ddd, 1H, J=1.65, 7.26, 8.91Hz), 7.10-7.03(m, 3H), 6.94-6.86(m, 3H), 4.10(t, 2H, J=5.94Hz), 3.89(s, 3H), 3.69(s, 2H), 2.77(t, 2H, J=5.94Hz), 2.53-2.49(m, 4H), 1.57-1.65(m, 4H), 1.48-1.42(m, 2H).  

TABLE 62 415 43 ¹H-NMR (DMSO-d₆); δ 13.56(br, 1H), 11.16(brs, 1H), 11 8.47(d, 1H, J=8.58Hz), 8.09(s, 1H), 7.96(d, 1H, J=7.92Hz), 7.80(d, 1H, J=8.25Hz), 7.57(dd, 1H, J=7.59, 8.25Hz), 7.14(dd, 1H, J=7.59, 7.92Hz), 7.06-6.93(m, 5H), 4.08(t, 2H, J=3.96Hz), 3.76(s, 2H), 3.70(t, 2H, J=3.66Hz), 3.52(q, 2H, J=6.93Hz), 1.14(t, 3H, J=6.93Hz). 415 47 11.16(brs, 1H), 8.68(d, 1H, J=8.58Hz), 8.16(d, 1H, 10 methyl J=2.31Hz), 8.01(dd, 1H, J=1.65, 7.92Hz), 7.71(dd, 1H, ester J=2.31, 8.58Hz), 7.53(ddd, 1H, J=1.65, 7.25, 8.53Hz), 7.11-7.05(m, 3H), 6.94(d, 2H, J=8.90Hz), 6.87(d, 1H, J=8.58Hz), 4.12(t, 2H, J=462Hz), 3.89(s, 3H), 3.79(t, 2H, J=4.29Hz), 3.70(s, 2H), 3.61(q, 2H, J=6.93Hz), 1.25(t, 3H, J=6.93Hz). 416 41 ¹H-NMR (DMSO-d₆); δ 14.00-13.00(br, 1H), 11.20(brs, 11 1H), 8.46(d, 1H, J=8.58Hz), 8.09(d, 1H, J=2.31Hz), 7.95(d, 1H, J=8.25Hz), 7.80(dd, 1H, J=2.31, 8.58Hz), 7.57(dd, 1H, J=7.59, 8.25Hz), 7.14(dd, 1H, J=7.59, 7.59Hz), 6.91-7.07(m, 5H), 4.56-4.50(m, 1H), 3.90-3.82(m, 2H), 3.76(s, 2H), 3.52-3.44(m, 2H), 1.99-1.94(m, 2H), 1.66-1.52(m, 2H). 416 31 11.18(brs, 1H), 8.68(d, 1H, J=8.58Hz), 8.16(d, 1H, 10 methyl J=2.31Hz), 8.01(dd, 1H, J=1.65, 7.92Hz), 7.72(dd, 1H, ester J=2.31, 8.58Hz), 7.54(ddd, 1H, J=1.65, 6.93, 8.58Hz), 7.12-7.05(m, 3H), 6.95-6.87(m, 3H), 4.48-4.39(m, 1H), 4.03-3.92(m, 2H), 3.90(s, 3H), 3.70(s, 2H), 3.62-3.53(m, 2H), 2.06-1.99(m, 2H), 1.85-1.74(m, 2H). 417 68 ¹H-NMR (DMSO-d₆); δ 11.18(brs, 1H), 8.46(d, 1H, 11 J=7.59Hz), 8.09(d, 1H, J=1.98Hz), 7.95(d, 1H, J=7.92Hz), 7.80(dd, 1H, J=8.58, 1.65Hz), 7.56(dd, 1H, J=8.25, 7.59Hz), 7.28(dd, 2H, J=7.92, 7.26Hz), 7.14(dd, 1H, J=7.92, 7.26Hz), 7.07-6.89(m, 8H), 4.13(t, 4H, J=6.27Hz), 3.76(s, 2H), 2.17(m, 2H). 417 61 11.16(brs, 1H), 8.68(dd, 1H, J=8.58, 0.99Hz), 8.16(d, 1H, 10 methyl J=2.31Hz), 8.00(dd, 1H, J=7.92, 1.65Hz), 7.70(dd, 1H, ester J=8.25, 2.64Hz), 7.53(ddd, 1H, J=8.58, 7.25, 1.65Hz), 7.27(m, 2H), 7.08(m, 1H), 7.06(d, 2H, J=8.90Hz), 6.96-6.77(m, 6H), 4.16(t, 2H, J=5.94Hz), 4.15(t, 2H, J=5.94Hz), 3.88(s, 3H), 3.69(s, 2H), 2.26(quint, 2H, J=5.94Hz).  

TABLE 63 418 17 ¹H-NMR (DMSO-d₆); δ 11.33(brs, 1H), 8.45(d, 1H, 11 yield J=8.57Hz), 8.08(s, 1H), 7.95(d, 1H, J=7.59Hz), 7.79(d, from 1H, J=8.25Hz), 7.55(dd, 1H, J=8.25, 7.58Hz), 7.12(dd, Ex.6 1H, J=7.59, 7.26Hz), 7.06-6.92(m, 5H), 4.05(t, 2H, J=4.62Hz), 3.75(s, 2H), 3.69(t, 2H, J=3.96Hz), 3.63(m, 1H), 1.11(d, 6H, J=5.94Hz). 419 23 ¹H-NMR (DMSO-d₆); δ 11.19(brs, 1H), 8.46(d, 1H, 11 yield J=8.25Hz), 8.09(d, 1H, J=2.31Hz), 7.95(dd, 1H, J=7.92, from 1.65Hz), 7.80(dd, 1H, J=8.58, 1.98Hz), 7.56(dd, 1H, Ex.6 J=8.25, 7.26Hz), 7.13(dd, 1H, J=7.59, 7.59Hz), 7.05(d, 2H, J=8.91Hz), 6.97(d, 2H, J=8.91Hz), 6.92(d, 1H), 4.11(t, 2H, J=4.95Hz), 3.80(t, 2H, J=4.62Hz), 3.75(br, 6H). 420 50 ¹H-NMR (DMSO-d₆); δ 11.93(brs, 1H), 8.45(d, 1H, 11 J=8.24Hz), 8.08(s, 1H), 7.96(d, 1H, J=7.92Hz), 7.79(dd, 1H J=8.25, 1.65Hz), 7.49(dd, 1H, J=7.92, 7.92Hz), 7.12-6.91(m, 6H), 4.06(t, 2H, J=4.29Hz), 3.74(t, 2H), 3.72(s, 2H), 3.32(m, 1H), 1.85(m, 2H), 1.66(m, 2H), 1.21(m, 6H). 420 86 11.16(brs, 1H), 8.67(d, 1H, J=8.58Hz), 8.16(d, 1H, 10 methyl J=2.31Hz), 8.00(dd, 1H, J=7.91, 1.65Hz), 7.71(dd, 1H, ester J=8.58, 2.31Hz), 7.52(ddd, 1H, J=8.58, 7.25, 1.65Hz), 7.07(m, 1H), 7.06(d, 2H, J=8.91Hz), 6.93(d, 2H, J=9.23Hz), 6.86(d, 1H, J=8.25Hz), 4.10(t, 2H, J=4.95Hz), 3.89(s, 3H), 3.80(t, 2H, J=4.62Hz), 3.69(s, 2H), 3.29(m, 1H), 1.92-1.80(m, 2H), 1.75-1.60(m, 2H), 1.34-1.20(m, 6H). 421 65 ¹H-NMR (DMSO-d₆); δ 11.23(brs, 1H), 8.46(d, 1H, 11 J=8.41Hz), 8.09(s, 1H), 7.95(d, 1H, J=7.75Hz), 7.80(dd, 1H, J=8.58, 2.64Hz), 7.56(dd, 1H, J=7.75, 7.26Hz), 7.10(dd, 1H, J=7.75, 7.59Hz), 7.05-6.93(m, 5H), 4.36(m, 1H), 3.75(s, 2H), 3.24(s, 3H), 3.21(m, 1H), 1.98(m, 2H), 1.67(m, 4H), 1.42(m, 2H). 421 71 11.16(brs, 1H), 8.68(d, 1H, J=8.41Hz), 8.16(d, 1H, 10 methyl J=2.31Hz), 8.00(dd, 1H, J=7.92, 1.65Hz), 7.71(dd, 1H, ester J=8.41, 2.48Hz), 7.52(ddd, 1H, J=8.74, 7.09, 1.65Hz), 7.16-7.02(m, 3H), 6.97-6.82(m, 3H), 4.30(m, 1H), 3.88(s, 3H), 3.69(s, 2H), 3.33(s, 3H), 3.30(m, 1H), 2.09-1.25(m, 8H).  

TABLE 64 422 43 ¹H-NMR (DMSO-d₆); δ 11.19(brs, 1H), 8.46(d, 1H, 11 J=8.08Hz), 8.08(s, 1H), 7.95(dd, 1H, J=7.92, 1.65Hz), 7.80(dd, 1H, J=8.58, 2.31Hz), 7.56(dd, 1H, J=8.58, 7.26Hz), 7.13(dd, 1H, J=7.59, 7.59Hz), 7.07-6.92(m, 5H), 4.08(t, 2H, J=4.45Hz), 3.76(s, 2H), 3.72(t, 2H), 3.59(t, 2H, J=3.29Hz), 3.50(t, 2H, J=2.64Hz), 3.44(q, 2H, J=7.09Hz), 1.10(t, 3H, J=7.09Hz). 422 80 11.16(brs, 1H), 8.68(dd, 1H, J=8.58, 0.99Hz), 8.16(d, 1H, 10 methyl J=2.47Hz), 8.00(dd, 1H, J=7.92, 1.65Hz), 7.71(dd, 1H, ester J=8.41, 2.47Hz), 7.51(ddd, 1H, J=8.58, 7.25, 1.65Hz), 7.10-7.02(m, 3H), 6.95-6.85(m, 3H), 4.13(t, 2H, J=5.11Hz), 3.89(s, 3H), 3.86(m, 2H), 3.71(m, 2H), 3.69(s, 2H), 3.61(m, 2H), 3.54(q, 2H, J=6.93Hz), 1.21(t, 3H, J=6.93Hz). 423 50 ¹H-NMR (DMSO-d₆); δ 11.66(brs, 1H), 8.66(d, 1H, 11 J=8.74Hz), 8.46(s, 1H), 8.01(d, 1H, J=8.24Hz), 7.91(dd, 1H, J=8.74, 2.64Hz), 7.51(dd, 1H, J=8.90, 7.25Hz), 7.10-6.97(m, 3H), 6.93(d, 2H, J=9.07Hz), 6.83(d, 1H, J=8.57Hz), 4.07(t, 2H, J=4.61Hz), 3.75(t, 2H), 3.72(s, 2H), 3.44(s, 3H). 423 86 11.15(brs, 1H), 8.67(d, 1H, J=8.57Hz), 8.16(d, 1H, 10 methyl J=2.14Hz), 7.98(dd, 1H, J=7.92, 2.80Hz), 7.70(dd, 1H, ester J=8.41, 2.31Hz), 7.51(ddd, 1H, J=8.58, 7.25, 1.65Hz), 7.09-7.05(m, 3H), 6.97-6.79(m, 3H), 4.10(dd, 2H, J=6.10, 4.62Hz), 3.88(s, 3H), 3.73(dd, 2H, J=5.77, 4.78Hz), 3.69(s, 2H), 3.44(s, 3H). 424 62 11.11(brs, 1H), 8.45(d, 1H, J=8.74Hz), 8.09(s, 1H), 11 7.95(d, 1H, J=7.91Hz), 7.79(dd, 1H, J=8.57, 2.47Hz), 7.56(dd, 1H, J=8.08, 7.75Hz), 7.13(dd, 1H, J=7.91, 6.26Hz), 7.06-6.90(m, 5H), 4.08(t, 2H, J=4.45Hz), 3.75(s, 2H), 3.69(t, 2H, J=3.95Hz), 3.46(t, 2H, J=6.26Hz), 1.50(m, 2H), 1.34(m, 2H), 0.88(t, 3H, J=7.26Hz). 424 75 11.16(brs, 1H), 8.67(d, 1H, J=8.41Hz), 8.16(d, 1H, 10 methyl J=2.47Hz), 8.00(dd, 1H, J=7.92, 1.65Hz), 7.71(dd, 1H, ester J=8.41, 2.31Hz), 7.52(ddd, 1H, J=8.58, 7.56, 1.65Hz), 7.10-7.04(m, 3H), 6.93(d, 2H, J=9.07Hz), 6.87(d, 1H, J=8.41Hz), 4.11(t, 2H, J=4.62Hz), 3.88(s, 3H), 3.77(t, 2H, J=4.45Hz), 3.69(s, 2H), 3.53(t, 2H, J=6.60Hz), 1.59(m, 2H), 1.37(m, 2H), 0.92(t, 3H, J=7.26Hz).  

TABLE 65 425 76 ¹H-NMR (DMSO-d₆); δ 11.12(brs, 1H), 8.46(d, 1H, 11 J=8.24Hz), 8.09(d, 1H, J=2.64Hz), 7.95(dd, 1H, J=7.91, 1.81Hz), 7.80(dd, 1H, J=8.41, 2.63Hz), 7.57(dd, 1H, J=8.74, 7.25Hz), 7.13(dd, 1H, J=7.91, 7.25Hz), 7.06-6.92(m, 5H), 4.08(t, 2H, J=4.28Hz), 3.76(s, 2H), 3.74(t, 2H, J=4.28Hz), 3.59(t, 2H, J=3.13Hz), 3.47(t, 2H, J=2.80Hz), 3.25(s, 3H). 425 83 11.15(brs, 1H), 8.67(d, 1H, J=8.58Hz), 8.16(d, 1H, 10 methyl J=2.47Hz), 7.99(dd, 1H, J=7.92, 1.32Hz), 7.68(m, 1H), ester 7.51(m, 1H), 7.28-7.01(m, 3H), 6.95-6.77(m, 3H), 4.13(t, 2H, J=5.11Hz), 3.88(s, 3H), 3.87(t, 2H, J=5.60Hz), 3.72(t, 2H, J=5.11Hz), 3.69(s, 2H), 3.57(t, 2H, J=5.11Hz), 3.39(s, 3H). 426 86 ¹H-NMR (DMSO-d₆); δ 11.19(brs, 1H), 8.45(d, 1H, 11 J=8.57Hz), 8.08(s, 1H), 7.95(d, 1H, J=7.92Hz), 7.80(dd, 1H, J=8.57, 2.63Hz), 7.56(dd, 1H, J=8.90, 6.76Hz), 7.13(dd, 1H, J=7.75, 7.42Hz), 7.06-6.92(m, 5H), 4.08(t, 2H, J=4.28Hz), 3.75(s, 2H), 3.69(t, 2H, J=3.46Hz), 3.41(t, 2H, J=6.59Hz), 1.52(m, 2H), 0.87(t, 3H, J=7.25Hz). 426 80 11.16(brs, 1H), 8.68(d, 1H, J=8.41Hz), 8.16(d, 1H, 10 methyl J=2.31Hz), 8.00(dd, 1H, J=7.92, 1.65Hz), 7.71(dd, 1H, ester J=8.41, 2.47Hz), 7.52(m, 1H), 7.10-7.03(m, 3H), 6.93(d, 2H, J=8.91Hz), 6.87(d, 1H, J=8.41Hz), 4.11(t, 2H, J=5.11Hz), 3.89(s, 3H), 3.78(t, 2H, J=5.11Hz), 3.69(s, 2H), 3.49(t, 2H, J=6.59Hz), 1.62(m, 2H), 0.93(t, 3H, J=7.42Hz). 427 79 11.69(brs, 1H), 8.46(d, 1H, J=8.4Hz), 8.11(d, 1H, J=2.2Hz), 11 7.96(dd, 1H, J=7.8Hz), 7.77-7.87(m, 3H), 7.56(d, 1H, J=2.4Hz), 7.52(dd, 1H, J=7.8, 7.3Hz), 7.39(d, 1H, J=2.4Hz), 7.27(dd, 1H, J=8.6, 2.2Hz), 7.18(dd, 1H, J=8.9, 2.4Hz), 7.11(dd, 1H, J=8.4, 7.3Hz), 7.04(d, 1H, J=8.1Hz), 4.23(t, 2H, J=5.7Hz), 3.76(s, 2H), 3.60-3.63(m, 4H), 2.83(t, 2H, J=5.7Hz), 2.56-2.59(m, 4H). 427 56 11.17(brs, 1H), 8.69(d, 1H, J=8.6Hz), 8.17(s, 1H), 10 methyl 7.98-8.02(m, 1H), 7.64-7.76(m, 3H), 7.49-7.52(m, 2H), ester 7.25-7.30(m, 1H), 7.07-7.17(m, 3H), 6.93-6.96(m, 1H), 4.20-4.24(m, 2H), 3.89(s, 3H), 3.73-3.77(m, 4H), 3.71(s, 2H), 2.84-2.88(m, 2H), 2.59-2.62(m, 4H).  

TABLE 66 428 57 10.76(brs, 1H), 8.76(d, 1H, J=7.58Hz), 8.10(dd, 1H, 11 J=7.92, 1.65Hz), 7.59(ddd, 1H, J=8.58, 7.26, 1.65Hz), 7.44(dd, 1H, J=1.98, 0.99Hz), 7.29(d, 2H, J=8.58Hz), 7.09(ddd, 1H, J=7.91, 7.26, 0.99Hz), 6.98(d, 2H, J=8.58Hz), 6.94-6.84(m, 4H), 6.42-6.37(m, 2H), 4.93(s, 2H), 3.76(s, 2H). 428 35 11.03(brs, 1H), 8.71(d, 1H, J=8.25Hz), 7.99(dd, 1H, 10 methyl J=7.91, 1.65Hz), 7.52(ddd, 1H, J=8.58, 7.25, 1.65Hz), ester 7.45(dd, 1H, J=1.65, 0.66Hz), 7.31(d, 2H, J=8.58Hz), 7.06(dd, 1H, J=7.26, 6.92Hz), 7.01-6.87(m, 6H), 6.43-6.37(m, 2H), 4.98(s, 2H), 3.87(s, 3H), 3.73(s, 2H). 981 75 13.51(br, 1H), 11.16(brs, 1H), 9.31(brs, 1H), 8.47(d, 1H, 11 J=7.6Hz), 8.08(s, 1H), 7.95(d, 1H, J=7.9Hz), 7.77(d, 1H, J=8.6Hz), 7.56(t, 1H, J=7.9Hz), 7.13(t, 1H, J=7.9Hz), 6.94-6.87(m, 3H), 6.77(d, 2H, J=8.9Hz), 3.75(s, 2H). 982 30 11.77(brs, 1H), 8.66(d, 1H, J=8.3Hz), 8.51(s, 1H), 8.02(d, 11 1H, J=7.9Hz), 7.94(d, 1H, J=8.9Hz), 7.51(t, 1H, J=7.1Hz), 7.01-7.09(m, 3H), 6.83-6.88(m, 3H), 4.68(brm, 1H), 3.73(s, 2H), 1.4-2.0(brm, 8H). 983 41 ¹H-NMR (DMSO-d₆); δ 11.27(brs, 1H), 8.55(d, 1H, 11 J=8.25Hz), 8.18(d, 1H, J=1.98Hz), 8.04(dd, 1H, J=1.32, 7.92Hz), 7.89(dd, 1H, J=2.31, 8.25Hz), 7.66(ddd, 1H, J=1.32, 6.92, 8.58Hz), 7.23(dd, 1H, J=6.93, 7.59Hz), 7.12(d, 2H, J=9.24Hz), 7.03(d, 1H, J=8.24Hz), 6.99(d, 2H, J=8.91Hz), 4.53(m, 1H), 3.85(s, 2H), 2.01-1.50(m, 14H). 984 38 ¹H-NMR (DMSO-d₆); δ 13.66(br, 1H), 11.27(brs, 1H), 11 8.55(d, 1H, J=8.25Hz), 8.18(d, 1H, J=2.31Hz), 8.05(dd, 1H, J=1.32, 7.92Hz), 7.89(dd, 1H, J=2.31, 8.25Hz), 7.66(dd, 1H, J=6.93, 7.25Hz), 7.23(t, 1H, J=7.26Hz), 7.12(d, 2H, J=8.91Hz), 7.04(d, 1H, J=8.57Hz), 7.03(d, 2H, J=8.80Hz), 4.25(m, 1H), 3.85(s, 2H), 1.70(m, 4H), 1.00(t, 6H, J=7.26Hz). 985 35 ¹H-NMR (DMSO-d₆); δ 14.15(brs, 1H), 8.40(d, 1H, 11 J=7.92Hz), 8.05(d, 1H, J=1.98Hz), 8.00(d, 1H, J=7.59Hz), 7.77(dd, 1H, J=2.31, 8.58Hz), 7.27(dd, 1H, J=7.26, 7.92Hz), 7.02-6.89(m, 6H), 4.27(m, 1H), 3.60(s, 2H), 1.89(m, 2H), 1.72(m, 2H), 1.53-1.23(m, 6H).  

TABLE 67 987 23 11.64(brs, 1H), 8.65(d, 1H, J=8.6Hz), 8.45(s, 1H), 8.04(d, 11 1H, J=7.9Hz), 7.91(d, 1H, J=8.6Hz), 7.51(t, 1H, J=7.6Hz), 7.06(m, 1H), 7.03(d, 2H, J=8.9Hz), 6.90-6.82(m, 3H), 3.86(m, 1H), 3.74(s, 2H), 1.80-1.60(brm, 4H), 1.55-1.20(br, 18H). 990 86 11.72(brs, 1H), 8.66(d, 1H, J=8.3Hz), 8.48(d, 1H, J=2.0Hz), 11 8.01(dd, 1H, J=1.3, 7.9Hz), 7.93(dd, 1H, J=2.3, 8.6Hz), 7.51(dt, 1H, J=1.3, 7.9Hz), 7.03-7.07(m, 1H), 7.04(d, 2H, J=9.2Hz), 6.89(d, 2H, J=8.9Hz), 6.83(d, 1H, J=8.6Hz), 5.19(t, 1H, J=7.1Hz), 3.88(t, 2H, J=7.1Hz), 3.73(s, 2H), 2.46(q, 2H, J=6.9Hz), 1.73(s, 3H), 1.66(s, 3H). 991 97 11.71(brs, 1H), 8.66(d, 1H, J=8.6Hz), 8.48(s, 1H), 8.01(d, 11 1H, J=1.6, 7.9Hz), 7.93(dd, 1H, J=2.3, 8.6Hz), 7.51(t, 1H, J=7.2Hz), 7.09-7.06(m, 1H), 7.05(d, 2H, J=8.9Hz), 6.92(d, 2H, J=9.2Hz), 6.85(d, 1H, J=8.6Hz), 6.10-5.96(m, 1H), 5.40(m, 1H), 5.28(m, 1H), 4.48(dd, 2H, J=1.3, 4.8Hz), 3.73(s, 2H). 992 69 11.68(sbr, 1H), 8.66(d, 1H, J=8.3Hz), 8.48(d, 1H, J=2.3Hz), 11 8.01(d, 1H, J=7.9Hz), 7.92(dd, 1H, J=2.6, 8.6Hz), 7.51(t, 1H, J=7.2Hz), 7.06(m, 1H), 7.04(d, 2H, J=8.9Hz), 6.90(d, 2H, J=9.2Hz), 6.84(d, 1H, J=8.6Hz), 5.67-5.89(m, 2H), 4.40(d, 2H, J=5.9Hz), 3.73(s, 2H), 1.75(d, 3H, J=6.3Hz). 993 42 11.71(brs, 1H), 8.66(d, 1H, J=8.3Hz), 8.49(d, 1H, J=2.0Hz), 11 8.01(dd, 1H, J=1.7, 7.9Hz), 7.93(dd, 1H, J=2.0, 8.6Hz), 7.50(t, 1H, J=7.6Hz), 7.09-7.06(m, 1H), 7.04(d, 2H, J=9.2Hz), 6.92(d, 2H, J=9.2Hz), 6.84(d, 1H, J=8.6Hz), 5.08(s, 1H), 4.98(s, 1H, 4.38(s, 2H), 3.73(s, 2H), 1.81(s, 3H). 994 86 11.70(brs, 1H), 8.65(d, 1H, J=8.3Hz), 8.48(d, 1H, J=2.0Hz), 11 8.03(d, 1H, J=7.9Hz), 7.91(dd, 1H, J=2.3, 8.6Hz), 7.51(t, 1H, J=7.2Hz), 7.06-7.00(m, 1H), 7.01(d, 2H, J=8.3Hz), 6.91(d, 2H, J=9.2Hz), 6.83(d, 1H, J=8.6Hz), 5.47(t, 1H, J=6.2Hz), 5.09(t, 1H, J=6.2Hz), 4.49(d, 2H, J=6.2Hz), 3.73(s, 2H), 2.09(brm, 4H), 1.71(s, 3H), 1.68(s, 3H), 1.60(s, 3H). 1002 10 11.67(brs, 1H), 8.66(d, 1H, J=8.6Hz), 8.45(s, 1H), 11 8.02(dd, 1H, J=1.3, 7.9Hz), 7.91(dd, 1H, J=2.0, 8.6Hz), 7.54(t, 1H, J=7.2Hz), 7.09-6.82(m, 6H), 6.40-6.32(m, 1H), 5.97-5.84(m, 2H), 5.37-5.05(m, 3H), 4.52(d, J=4.3Hz, 1H), 3.72(s, 2H).  

TABLE 68 1017 60 ¹H-NMR (DMSO-d₆); δ 13.56(br, 1H), 11.18(brs, 1H), 11 8.46(d, 1H, J=8.57Hz), 8.08(s, 1H), 7.95(d, 1H, J=7.92Hz), 7.79(d, 1H, J=8.25Hz), 7.57(dd, 1H, J=7.26, 8.58Hz), 7.37(m, 2H), 7.16-6.92(m, 8H), 4.17(t, 2H, J=6.60Hz), 3.76(s, 2H), 3.03(t, 2H, J=6.60Hz). 1019 34 ¹H-NMR (DMSO-d₆); δ 14.26(br, 1H), 8.40(d, 1H, 11 J=7.92Hz), 8.19(d, 2H, J=7.26Hz), 8.05(s, 1H), 8.00(d, 1H, J=7.58Hz), 7.78(d, 1H, J=6.27Hz), 7.64(d, 2H, J=7.92Hz), 7.26(dd, 1H, J=6.93, 8.25Hz), 7.04-6.85(m, 5H), 6.77(d, 1H, J=7.91Hz), 4.26(t, 2H, J=6.6Hz), 3.61(s, 2H), 3.20(t, 2H, J=6.27Hz). 1021 82 13.56(br, 1H), 11.18(brs, 1H), 8.46(d, 1H, J=7.58Hz), 11 8.08(d, 1H, J=1.98Hz), 7.95(d, 1H, J=7.92Hz), 7.80(dd, 1H, J=1.98, 8.58Hz), 7.57(dd, 1H, J=7.59, 8.25Hz), 7.33-7.21(m, 5H), 7.13(dd, 1H, J=7.26, 7.92Hz), 7.06-6.92(m, 5H), 4.19(t, 2H, J=6.93Hz), 3.75(s, 2H), 3.04(t, 2H, J=6.93Hz). 1059 35 ¹H-NMR (DMSO-d₆); δ 8.81(d, 1H, J=1.65Hz), 8.70(d, 11 1H, J=7.91Hz), 8.43(dd, 1H, J=1.31, 8.24Hz), 8.14(d, 1H, J=7.59Hz), 7.53(m, 1H), 7.23-7.14(m, 4H), 7.06(d, 2H, J=9.24Hz), 4.30(m, 1H), 1.72(m, 4H), 1.02(t, 6H, J=7.26Hz). 1060 35 ¹H-NMR (DMSO-d₆); δ 8.80(d, 1H, J=2.31Hz), 8.71(d, 11 1H, J=8.57Hz), 8.41(dd, 1H, J=2.31, 8.57Hz), 8.14(d, 1H, J=8.58Hz), 7.64(dd, 1H, J=7.59, 7.91Hz), 7.27-7.10(m, 4H), 7.07(d, 2H, J=9.24Hz), 4.40(m, 1H), 2.08-1.36(m, 10H). 1061 25 ¹H-NMR (DMSO-d₆); δ 12.28(br, 1H), 8.78(d, 1H, 11 J=2.31Hz), 8.71(d, 1H, J=8.57Hz), 8.39(dd, 1H, J=2.96, 8.58Hz), 8.14(dd, 1H, J=1.65, 7.92Hz), 7.75(dd, 1H, J=7.26, 8.25Hz), 7.31(dd, 1H, J=6.60, 7.59Hz), 7.24(d, 1H, J=8.58Hz), 7.20(d, 2H, J=8.90Hz), 7.03(d, 2H, J=9.23Hz), 4.56(m, 1H), 2.00-1.55(m, 14H). 1077 100 11.16(brs, 1H), 8.69(d, 1H, J=8.58Hz), 8.18(d, 1H, 10 J=2.31Hz), 8.01(dd, 1H, J=1.65, 7.92Hz), 7.72(dd, 1H, J=2.31, 8.58Hz), 7.53(ddd, 1H, J=1.65, 7.26, 8.57Hz), 7.11-6.98(m, 3H), 6.92-6.86(m, 3H), 4.10(m, 1H), 3.89(s, 3H), 3.71(s, 2H), 1.68(m, 4H), 0.96(t, 6H, J=7.25Hz).  

TABLE 69 1079 89 11.16(brs, 1H), 8.69(d, 1H, J=8.3Hz), 8.17(d, 1H, J=2.3Hz), 10 8.00(dd, 1H, J=1.7, 7.9Hz), 7.70(dd, 1H, J=2.3, 8.9Hz), 7.50(t, 1H, J=7.1Hz), 7.06-7.10(m, 1H), 7.05(d, 2H, J=8.9Hz), 6.85-6.90(m, 3H), 4.72(brm, 1H), 3.89(s, 3H), 3.70(s, 2H), 1.8-2.0(brm, 4H), 1.5-1.75(brm, 4H). 1080 85 11.16(brs, 1H), 8.68(d, 1H, J=8.25Hz), 8.17(d, 1H, 10 J=2.64Hz), 8.01(dd, 1H, J=1.65, 8.25Hz), 7.71(dd, 1H, J=2.31, 8.58Hz), 7.53(ddd, 1H, J=1.65, 7.25, 8.58Hz), 7.27-7.02(m, 3H), 6.93-6.86(m, 3H), 3.97(m, 1H), 3.89(s, 3H), 3.70(s, 2H), 2.04-1.05(m, 10H). 1081 100 11.16(brs, 1H), 8.68(d, 1H, J=8.58Hz), 8.17(d, 1H, 10 J=2.31Hz), 8.01(dd, 1H, J=1.65, 7.92Hz), 7.71(dd, 1H, J=2.31, 8.58Hz), 7.53(ddd, 1H, J=1.65, 7.26, 8.57Hz), 7.11-7.03(m, 3H), 6.88-6.84(m, 3H), 4.36(m, 1H), 3.89(s, 3H), 3.70(s, 2H), 2.01-1.54(m, 14H). 1082 92 11.16(brs, 1H), 8.68(d, 1H, J=8.6Hz), 8.17(d, 1H, J=2.4Hz), 10 8.00(d, 1H, J=7.9Hz), 7.71(dd, 1H, J=2.3, 8.6Hz), 7.53(t, 1H, J=7.3Hz), 7.10-7.03(m, 3H), 6.92-6.86(m, 3H), 3.89(s, 3H), 3.84(m, 1H), 3.70(s, 2H), 1.80-1.60(brm, 4H), 1.55-1.20(br, 18H). 1083 33 11.16(brs, 1H), 8.68(d, 1H, J=8.58Hz), 8.16(d, 1H, 10 J=2.31Hz), 8.01(dd, 1H, J=1.65, 7.92Hz), 7.71(dd 1H, J=2.64, 8.58Hz), 7.53(ddd, 1H, J=1.65, 7.26, 8.57Hz), 7.11-7.04(m, 3H), 6.93-6.86(m, 3H), 3.89(s, 3H), 3.81(dd, 2H, J=5.61, 10.23Hz), 3.70(s, 2H), 1.56-1.23(m, 7H), 1.03-0.84(m, 6H). 1084 38 11.16(brs, 1H), 8.68(d, 1H, J=8.6Hz), 8.16(d, 1H, J=2.3Hz), 6 8.00(d, 1H, J=1.6, 7.9Hz), 7.71(dd, 1H, J=2.3, 8.6Hz), 7.52(t, 1H, J=7.2Hz), 7.11-7.05(m, 3H), 6.92(d, 2H, J=6.9Hz), 6.88(d, 1H, J=8.6Hz), 6.11-5.99(m, 1H), 5.46-5.37(m, 1H), 5.32-5.26(m, 1H), 4.52(d, 2H, J=5.9Hz), 3.89(s, 3H), 3.69(s, 2H).  

TABLE 70 1085 34 11.17(brs, 1H), 8.68(d, 1H, J=8.6Hz), 8.16(d, 1, J=2.3Hz, 6 H), 8.00(dd, 1H, J=1.6, 7.9Hz), 7.70(dd, 1H, J=2.3, 8.6Hz), 7.53(dt, 1H, J=1.3, 7.9Hz), 7.10-7.06(m, 1H), 7.06(d, 2H, J=9.2Hz), 6.90(d, 2H, J=8.9Hz), 6.89-6.85(m, 1H), 5.21(t, 1H, J=7.1Hz), 3.92(t, 2H, J=7.1Hz), 3.89(s, 3H), 3.70(s, 2H), 2.46(q, 2H, J=6.9Hz), 1.73(s, 3H), 1.66(s, 3H). 1086 39 11.17(brs, 1H), 8.68(d, 1H, J=8.6Hz), 8.16(s, 1H, 8.00(d, 10 1H, J=7.1Hz), 7.71(d, 1H, J=8.3Hz), 7.53(t, 1H, J=7.1Hz), 7.11-7.03(m, 3H), 6.96-6.85(m, 3H), 6.0-5.8(m, 2H), 5.4-5.1(m, 4H), 4.56(d, 1H, J=5.6Hz), 3.89(s, 3H), 3.70(s, 2H). 1087 41 11.16(brs, 1H, 8.68(d, 1H, J=8.6Hz), 8.16(d, 1H, J=2.3Hz), 10 8.00(dd, 1H, J=1.6, 7.9Hz), 7.71(dd, 1H, J=2.3, 8.6Hz), 7.53(t, 1H, J=7.8Hz), 7.11-7.06(m, 1H), 7.06(d, 2H, J=9.2Hz), 6.91(d, 2H, J=8.9Hz), 6.88(d, 1H, J=8.3Hz), 5.91-5.70(m, 2H), 4.44(d, 2H, J=5.6Hz), 3.89(s, 3H), 3.70(s, 2H), 1.76(dd, 3H, J=1.0, 5.3Hz). 1088 42 11.16(brs, 1H), 8.68(d, 1H, J=8.6Hz), 8.16(d, 1H, J=2.3Hz), 10 8.00(dd, 1H, J=1.6, 7.9Hz), 7.71(dd, 1H, J=2.3, 8.6Hz), 7.52(dt, 1H, J=1.6, 7.9Hz), 7.10-7.04(m, 3H), 6.93(d, 2H, J=8.9Hz), 6.88(d, 1H, J=8.6Hz), 5.10(s, 1H), 4.99(s, 1H), 4.42(s, 2H), 3.89(s, 3H), 3.70(s, 2H), 1.83(s, 3H). 1089 23 11.16(brs, 1H), 8.68(d, 1H, J=8.6Hz), 8.16(d, 1H, J=2.3Hz), 6 8.00(d, 1H, J=7.9Hz), 7.71(d, 1H, J=2.3, 8.6Hz), 7.52(t, 1H, J=7.9Hz), 7.08-7.11(m, 1H), 7.06(d, 2H, J=8.9Hz), 6.92(d, 2H, J=8.9Hz), 6.88(d, 1H, J=8.3Hz), 5.50(t, 1H, J=6.3Hz), 5.09(br, 1H), 4.52(d, 2H, J=6.6Hz), 3.89(s, 3H), 3.70(s, 2H), 2.05(brm, 4H), 1.73(s, 3H), 1.68(s, 3H), 1.60(s, 3H). 1090 49 11.16(brs, 1H), 8.68(d, 1H, J=8.25Hz), 8.16(d, 1H, 10 J=2.31Hz), 8.01(dd, 1H, J=1.65, 7.92Hz), 7.71(dd, 1H, J=2.31, 8.58Hz), 7.53(ddd, 1H, J=1.65, 7.26, 8.57Hz), 7.35-7.21(m, 5H), 7.11-7.04(m, 3H), 6.93-6.86(m, 3H), 4.17(t, 2H, J=6.92Hz), 3.89(s, 3H), 3.70(s, 2H), 3.10(t, 2H, J=6.92Hz).  

TABLE 71 1091 61 11.17(brs, 1H), 8.68(d, 1H, J=8.58Hz), 8.15(d, 1H, 10 J=2.31Hz), 8.01(dd, 1H, J=1.65, 7.92Hz), 7.71(dd, 1H, J=2.31, 8.58Hz), 7.53(ddd, 1H, J=1.32, 7.26, 8.57Hz), 7.25(m, 2H), 7.10-6.86(m, 8H), 4.14(t, 2H, J=6.93Hz), 3.89(s, 3H) 3.69(s, 2H), 3.06(t, 2H, J=6.93Hz). 1101 92 12.07(s, 1H), 8.90(d, 1H, J=2.63Hz), 8.88(d, 1H, J=8.25Hz), 10 8.32(dd, 1H, J=2.64, 8.58Hz), 8.08(dd, 1H, J=1.65, 7.92Hz), 7.60(ddd, 1H, J=1.65, 7.26, 8.58Hz), 7.16-6.93(m, 6H), 4.22(m, 1H), 3.94(s, 3H), 2.04-1.26(m, 10H). 1102 89 12.07(brs, 1H), 8.90(d, 1H, J=2.63Hz), 8.88(dd, 1H, 10 J=0.66, 8.58Hz), 8.31(dd, 1H, J=2.30, 8.57Hz), 8.07(dd, 1H, J=1.32, 7.92Hz), 7.60(ddd, 1H, J=1.32, 7.26, 8.58Hz), 7.15-7.06(m, 3H), 6.99(d, 1H, J=8.91), 6.90(d, 2H, J=8.91Hz), 4.39(m, 1H), 3.94(s, 3H), 2.04-1.41(m, 14H). 1103 65 12.08(brs, 1H), 8.90(d, 1H, J=2.63Hz), 8.88(dd, 1H, 10 J=0.66, 8.91Hz), 8.32(dd, 1H, J=2.65, 8.58Hz), 8.08(dd, 1H, J=1.65, 7.92Hz), 7.60(ddd, 1H, J=1.65, 7.26, 8.58Hz), 7.16-6.91(m, 6H), 4.09(m, 1H), 3.94(s, 3H), 1.70(m, 4H), 0.98(t, 6H, J=7.25Hz). 1105 100 11.16(brs, 1H), 8.69(d, 1H, J=8.58Hz), 8.18(d, 1H, 10 J=2.31Hz), 8.01(dd, 1H, J=1.65, 7.92Hz), 7.72(dd, 1H, J=2.31, 8.58Hz), 7.53(ddd, 1H, J=1.65, 7.26, 8.57Hz), 7.11-6.98(m, 3H), 6.92-6.86(m, 3H), 4.10(m, 1H), 3.89(s, 3H), 3.71(s, 2H), 1.68(m, 4H), 0.96(t, 6H, J=7.25Hz). 1108 30 11.16(brs, 1H), 8.67(d, 1H, J=8.25Hz), 8.15(d, 1H, 10 J=2.31Hz), 7.99(dd, 1H, J=1.32, 7.91Hz), 7.71(dd, 1H, J=2.31, 8.25Hz), 7.51(ddd, 1H, J=1.32, 7.25, 8.57Hz), 7.10-7.03(m, 3H), 6.94-6.87(m, 3H), 4.26(t, 2H, J=6.27Hz), 3.88(s, 3H), 3.69(s, 2H), 3.62(t, 2H, J=6.27Hz). 1118 60 ¹H-NMR (DMSO-d₆); δ 0.93(6H, t, J=7.81Hz), 1.67(4H, 11 dq, J=5.86, 7.81Hz), 3.77(2H, s), 4.37(1H, tt, J=5.86, 5.86Hz), 7.03(1H, d, J=7.81Hz), 7.15(2H, m), 7.25(1H, m), 7.35(1H, s), 7.54(1H, s), 7.57(1H, dd, J=7.81, 7.81Hz), 7.76(1H, d, J=9.76Hz), 7.83(2H, m), 7.95(1H, d, J=7.81Hz), 8.11(1H, s), 8.45(1H, d, J=9.76Hz), 11.13(1H, s), 13.56(1H, br).  

TABLE 72 1205 35 1.00(6H, t, J=7.51Hz), 1.74(4H, m), 3.71(2H, s), 3.90(3H, 10 s), 4.21(1H, m), 6.94(1H, d, J=6.94Hz), 7.11(3H, m), 7.26(1H, m), 7.50(2H, m), 7.70(3H, m), 8.02(1H, dd, J=1.73, 8.00Hz), 8.18(1H, d, J=2.47Hz), 8.69(1H, dd, J=0.91, 8.50Hz), 11.19(1H, s). 1243 41 11.16(brs, 1H), 8.68(d, 1H, J=8.6Hz), 8.16(d, 1H, J=2.3Hz), 10 8.00(dd, 1H, J=1.6, 7.9Hz), 7.71(dd, 1H, J=2.3, 8.6Hz), 7.53(t, 1H, J=7.8Hz), 7.11-7.06(m, 1H), 7.06(d, 2H, J=9.2Hz), 6.91(d, 2H, J=8.9Hz), 6.88(d, 1H, J=8.3Hz), 5.91-5.70(m, 2H), 4.44(d, 2H, J=5.6Hz), 3.89(s, 3H), 3.70(s, 2H), 1.76(dd, 3H, J=1.0, 5.3Hz). 1244 55 ¹H-NMR (DMSO-d₆); δ 14.25(brs, 1H), 8.41(d, 1H, 11 J=8.25Hz), 8.06(s, 1H), 8.00(d, 1H, J=7.91), 7.78(d, 1H, J=8.58Hz), 7.27(dd, 1H, J=7.26, 8.25Hz), 7.05-6.90(m, 6H), 3.83(dd, 2H, J=6.27, 10.23Hz), 3.61(s, 2H), 1.47-1.28(m, 7H), 1.00-0.89(m, 6H). 1245 41 ¹H-NMR (DMSO-d₆); δ 14.00-13.00(br, 1H), 11.20(brs, 11 1H), 8.46(d, 1H, J=8.58Hz), 8.09(d, 1H, J=2.31Hz), 7.95(d, 1H, J=8.25Hz), 7.80(dd, 1H, J=2.31, 8.58Hz), 7.57(dd, 1H, J=7.59, 8.25Hz), 7.14(dd, 1H, J=7.59, 7.59Hz), 6.91-7.07(m, 5H), 4.56-4.50(m, 1H), 3.90-3.82(m, 2H), 3.76(s, 2H), 3.52-3.44(m, 2H), 1.99-1.94(m, 2H), 1.65-1.52(m, 2H). Note: In the above tables, “methyl ester” means the carboxylic acid ester at the anthranilic acid site, and “methyl ester” and “ethyl ester” shown in the lower column mean carboxylic acid esters at the other site.  

TABLE 73 Compound Measured value Yield of Yield of No. M (M + 1)⁺ Example 10 Example 11 80 461.18 462.2 100 100 81 503.23 504.2 24 46 82 475.2 476.2 27 100 83 529.25 530.2 11 100 84 475.2 476.2 4 100 85 489.22 490.2 39 100  

TABLE 74 Compound Measured value Yield of Yield of No. M (M + 1)⁺ Example 6 Example 8 88 513.18 514.2 48 76  

TABLE 75 Yield (%) Com- Measured Acylation Hydrolysis 1st and Exam- pound value yield (%) yield (%) 2nd ple No. M (M + 1)⁺ 1st stage 2nd stage stages No. 52 474.18 475.2 73 100 73 25 53 490.17 491.2 87 100 87 25 54 536.19 537.4 84 100 84 25 55 474.18 475.2 67 100 67 25 56 490.17 491.2 55 100 55 25 57 536.19 537.4 58 100 58 25 58 488.19 489 73 91 66 25 59 504.19 505 75 88 66 25 60 550.21 551 30 44 13 25 61 488.19 489 56 58 29 25 62 504.19 505 61 77 47 25 63 550.21 551 82 81 66 25 64 502.21 503 65 63 41 25 65 564.23 565 76 52 40 25 66 518.21 519 56 65 36 25 67 502.21 503 41 84 34 25 68 564.23 565 87 85 74 25 69 518.21 519 71 77 55 25 70 502.21 503 59 96 56 25 71 564.23 565 72 88 63 25 72 518.21 519 78 99 77 25  

TABLE 76 73 502.21 503 51 91 46 25 74 564.23 565 70 94 66 25 75 518.21 519 71 61 43 25 76 488.19 489.2 70 100 70 25 77 550.21 551.2 45 100 45 25 78 488.19 489.2 61 100 61 24 79 504.19 505.2 59 100 59 25 95 502.21 503.3 78 51 39 21 96 564.23 565.3 100 50 51 20 97 578.24 579.3 100 63 63 21 98 594.24 595.3 100 65 65 21 99 598.19 599.3 99 46 45 21 100 632.52 633.3 100 60 60 21 101 565.22 566.3 82 45 37 21 102 565.22 566.3 56 22 13 21 103 516.23 517.3 72 32 23 21 104 530.24 531.3 70 57 40 21 105 560.24 531.3 79 63 50 21 106 544.26 545.3 98 77 76 21 107 544.26 545.3 84 47 40 21 108 544.26 545.3 89 63 56 21 109 586.3 587.3 94 94 89 21  

TABLE 77 110 570.27 571.3 83 76 64 21 111 609.21 610.3 100 32 32 21 112 578.24 579.3 78 45 35 21 113 594.24 595.3 86 94 81 21 114 592.26 593.3 89 60 53 21 115 554.21 555.0 96 51 49 21 116 567.2 568.3 26 27 7 21 117 538.18 539.3 96 63 61 21 118 552.19 553.3 88 54 48 21 119 566.21 567.3 90 43 39 21 120 580.22 581.3 68 50 34 21 121 600.19 601.3 100 63 63 21 122 614.21 615.3 88 68 61 21 123 634.15 635.3 92 65 60 21 124 668.12 669.3 93 52 49 21 125 645.18 646.3 96 2 2 21 126 614.21 615.3 34 13 5 21 127 518.21 519.3 30 71 21 21 128 532.22 533.3 62 48 30 21 129 546.24 547.3 38 14 5 21 130 546.24 547.3 31 61 19 21 131 560.25 561.3 49 45 22 21 132 560.25 561.3 14 16 2 21  

TABLE 78 133 560.25 561.3 35 49 17 21 134 594.24 595.3 41 65 27 21 135 573.25 574.3 27 72 20 21 136 545.25 546.3 45 69 31 21 137 545.25 546.3 32 67 22 21 138 579.24 580.3 19 69 13 21 139 593.25 594.3 6 99 6 21 140 609.25 610.3 13 79 11 21 141 613.2 614.3 19 89 17 21 142 647.16 648.3 27 61 17 21 143 624.22 625.3 21 60 13 21 144 593.25 594.3 34 95 32 21 145 629.25 630.3 40 62 25 21 146 579.24 580.3 78 54 42 23 147 593.25 594.3 72 60 43 23 148 607.27 608.3 67 50 34 23 149 588.17 589.3 88 61 54 23 150 553.22 554.3 78 88 69 23 151 580.22 581.3 69 61 42 23 152 580.22 581.3 98 61 60 23 153 580.22 581.3 87 77 67 23 154 579.24 580.3 83 40 33 23 155 579.24 580.3 76 73 55 23  

TABLE 79 156 593.25 594.3 78 69 54 23 157 607.27 608.3 79 34 27 23 158 607.27 608.3 70 60 42 23 159 621.25 622.3 100 66 66 23 160 621.25 622.3 100 59 59 23 161 606.24 607.3 89 72 64 23 162 610.21 611.3 81 73 59 23 163 622.13 623.3 100 54 54 23 164 604.22 605.3 88 62 55 23 165 567.24 568.3 61 57 35 23 166 603.24 604.3 100 62 62 23 167 617.25 618.3 71 57 40 23 168 603.24 604.3 46 17 8 23 169 603.24 604.3 71 74 53 23 170 603.24 604.3 67 53 36 23 171 554.22 555 74 74 55 23 172 604.24 605.3 85 56 48 23 173 605.23 606.3 34 66 22 23 174 604.14 605 81 64 52 23 175 578.24 579.3 — — 14 21 176 578.24 579.3 57 71 40 21 177 594.24 595.3 31 55 17 21 178 608.22 609.3 29 63 18 21  

TABLE 80 179 582.22 583.3 43 62 27 21 180 582.22 583.3 59 75 44 21 181 598.19 599.3 43 73 31 21 182 598.19 599.3 61 85 52 21 183 642.16 645.3 63 62 39 21 184 632.21 633.3 69 49 34 21 185 632.21 633.3 66 64 42 21 186 648.21 649.3 59 61 36 21 187 648.21 649.3 46 62 29 21 188 648.21 649.3 48 37 18 21 189 608.64 609 54 60 32 21 190 589.22 590.3 29 77 22 21 191 589.22 590.3 22 46 10 21 192 640.26 641.3 53 71 38 21 193 614.24 615.3 47 72 34 21 194 614.24 615.3 43 68 29 21 195 632.15 633 53 75 40 21 196 599.18 600 17 89 15 21 197 570.18 571 43 65 28 21 198 620.20 621.3 50 69 35 21 199 528.23 529 57 85 48 21 200 528.23 529.3 20 77 15 21 201 542.24 543.3 27 66 18 21  

TABLE 81 202 614.21 615.3 44 65 29 21 203 614.21 615.3 41 69 28 21 204 660.21 661.3 36 72 26 21 205 660.21 661.3 35 73 26 21 206 618.18 619.3 46 59 27 21 207 618.18 619.3 43 78 33 21 208 618.18 619.3 39 69 27 21 209 634.15 635 42 65 27 21 210 634.15 635 43 45 19 21 211 678.12 681 47 56 26 21 212 668.18 669.3 46 80 37 21 213 668.18 669.3 41 81 33 21 214 668.18 669.3 47 37 17 21 215 684.18 685 63 39 25 21 216 614.21 626.3 46 85 39 21 217 625.19 626.3 86 14 12 21 218 678.17 679.3 24 6 1 21 219 593.25 594.3 23 42 10 21 220 593.25 594.3 38 6 2 21 221 597.23 598.3 47 58 27 21 222 597.23 598.3 31 36 11 21 223 597.23 598.3 18 46 8 21 224 613.2 614.3 48 71 34 21  

TABLE 82 225 613.2 614.3 29 66 19 21 226 657.17 660 19 44 8 21 227 609.25 610.3 38 38 14 21 228 609.25 610.3 20 71 14 21 229 647.22 648.3 57 34 19 21 230 647.22 648.3 48 28 13 21 231 663.22 664.3 49 29 14 21 232 663.22 664.3 39 37 14 21 233 604.23 605 7 15 1 21 234 625.22 626.3 35 18 6 21 235 625.22 626.3 — — 23 21 236 621.25 622.3 12 66 8 21 237 621.25 622.3 10 71 7 21 238 632.21 633.3 39 80 31 21 239 514.21 515.3 — — 7 21 240 599.18 600.3 35 20 7 21 241 633.14 630.3 40 100 40 21 242 633.14 630.3 50 54 27 21 243 611.21 612.3 19 43 8 21 244 657.25 658.3 58 69 40 21 245 667.22 664.3 73 45 33 21 246 599.18 600.3 11 100 11 21 247 613.2 614.3 35 97 34 21  

TABLE 83 248 714.15 715 77 86 66 21 249 638.1 639 77 83 64 21 250 648.15 649.3 20 59 12 21 251 633.14 634 100 58 58 21 252 629.19 630.3 97 57 55 21 254 565.22 566.3 100 90 90 22 255 618.13 619.3 90 88 79 21 256 586.18 587.3 68 95 65 21 257 654.1 655 66 84 55 21 258 633.14 634.3 83 87 72 21 259 646.2 647.3 76 82 62 21 260 604.17 605.3 78 92 72 21 261 604.17 605.3 74 87 64 21 262 654.16 655.3 81 91 74 21 263 670.16 671.3 79 91 72 21 264 611.17 612.3 86 85 73 21 265 579.24 580.3 100 96 96 21 266 603.24 604.3 100 82 82 21 267 632.15 633.3 100 88 88 21 268 600.19 601.3 91 99 90 21 269 668.12 669.3 91 86 78 21 270 647.16 648.3 88 88 77 21 271 660.21 661.3 92 84 77 21  

TABLE 84 272 618.18 619.3 85 89 76 21 273 618.18 619.3 81 86 70 21 274 668.18 669.3 95 86 82 21 275 684.18 685.3 87 92 80 21 276 625.19 626.3 92 87 80 21 277 593.25 594.3 100 94 94 23 278 617.25 618.3 100 98 98 23 279 564.23 565.3 99 76 75 21 280 584.17 585.3 100 88 88 21 281 618.13 619.3 100 86 86 21 282 580.22 581.3 69 80 55 21 283 572.29 573.3 100 80 80 21 284 580.22 581.3 100 85 85 21 285 551.21 552.3 71 64 45 21 286 551.21 552.3 72 65 47 21 287 516.23 517.3 45 60 27 21 288 530.24 531.3 39 59 23 21 289 530.24 531.3 — — 68 21 290 628.14 631.3 100 75 75 21 291 618.2 619.3 100 82 82 21 292 634.19 635.3 100 78 78 21 293 606.18 607.3 100 83 83 21 294 600.19 601.3 99 37 37 21  

TABLE 85 295 620.14 621.3 98 74 73 21 296 654.1 655.3 93 69 64 21 297 566.21 567.3 96 71 68 21 298 586.18 587.3 95 72 68 21 299 646.2 647.3 88 92 81 21 300 646.2 647.3 89 81 72 21 301 604.17 605.3 87 93 81 21 302 654.16 655.3 88 88 77 21 303 670.16 671.3 85 100 85 21 304 611.17 612.3 88 100 88 21 306 595.23 596.3 59 100 59 21 308 610.21 611.3 86 100 86 21 309 599.18 600.3 78 98 76 21 310 531.24 532.3 60 81 49 21 311 643.15 644.3 85 89 76 21 312 649.2 650.3 89 100 89 21 313 590.22 591.3 — — 52 21 314 546.24 547.3 82 100 82 21 315 566.21 567.3 100 82 82 23 316 579.24 580.3 81 92 74 23 317 593.25 594 46 99 45 23 318 608.11 609 100 82 82 23 319 603.24 604.3 63 100 63 23  

TABLE 86 320 590.13 591.3 74 96 71 23 321 619.13 616.3 77 100 77 21 322 619.13 616.3 87 82 71 21 323 643.23 644.3 100 76 76 21 324 585.17 586 — — 92 21 325 599.18 600.3 — — 80 21 326 700.14 701 — — 84 21 327 634.14 635 75 88 66 21 328 619.13 620.3 100 85 85 21 329 682.16 683.3 97 56 54 21 330 630.24 631.3 70 58 41 21 331 650.21 651.3 98 32 31 21 332 664.22 665.3 8 37 3 21 333 684.17 685.3 10 66 7 21 334 718.13 719 100 43 43 21 335 643.27 644.5 9 49 4 21 336 697.17 698.3 100 57 57 21 337 674.24 675.3 8 25 2 21 338 615.24 616.3 75 51 38 21 339 615.24 616.3 89 45 40 21 340 566.24 567.3 4 68 3 21 341 580.26 581.3 86 53 46 21 342 594.69 595.3 90 37 33 21  

TABLE 87 343 594.27 595.3 100 41 41 21 344 636.32 637.3 100 62 62 21 345 644.25 645.3 100 18 18 21 346 616.22 617.3 7 28 2 21 347 610.27 611.3 100 48 48 21 348 623.26 624.3 2 94 2 21 349 595.27 596.3 21 55 12 21 350 649.2 650.3 93 57 53 21 352 661.22 662 59 73 43 21 353 707.26 708.3 95 59 56 21 354 649.2 650.3 96 49 47 21 355 663.21 664.3 100 49 49 21 356 764.17 765.3 55 56 31 21 357 698.17 699.3 — — 16 21 358 683.16 684.3 — — 17 21 359 679.21 680.3 89 52 46 21 360 614.24 615.3 100 14 14 21 361 634.19 635.3 46 58 27 21 362 668.15 669.3 83 50 42 21 363 630.24 631.3 62 84 52 21 364 622.3 623.3 64 95 61 21 365 630.24 631.3 73 83 61 21 366 601.22 602.3 49 57 28 21  

TABLE 88 367 601.22 602.3 52 87 45 21 368 566.24 567.3 69 46 32 21 369 580.26 581.3 59 82 48 21 370 580.26 581.3 64 92 59 21 371 678.16 681.3 98 66 65 21 372 668.21 669.3 76 51 39 21 373 684.21 685.3 100 83 83 21 374 656.2 657.3 100 76 76 21 375 616.22 617.3 100 73 73 23 376 629.25 630.3 82 64 52 23 377 643.27 644.3 46 78 36 23 378 658.13 659 100 80 80 23 379 653.25 684.3 97 63 61 23 380 640.14 641.3 100 60 60 23 381 650.21 651.3 90 60 54 21 382 670.15 671.3 76 90 68 21 383 704.12 705.2 67 89 60 21 384 616.22 617.3 82 47 39 21 385 636.19 637.3 85 59 50 21 386 696.21 697.2 79 93 73 21 387 696.21 697.4 96 74 71 21 388 654.18 655.3 97 75 73 21 389 704.18 705.2 82 78 64 21  

TABLE 89 390 720.18 721.4 90 79 71 21 391 661.19 663.3 93 76 71 21 392 629.25 630.3 93 72 67 21 393 645.25 646.3 76 90 68 21 394 683.16 684.3 69 51 35 21 395 660.22 661.3 40 34 14 21 396 649.2 650.3 56 64 36 21 397 581.25 582.3 64 43 28 21 398 693.17 696.4 30 63 19 21 399 699.22 700.4 63 66 42 21 400 640.23 641.5 18 34 6 21 401 596.25 597.4 75 60 45 21 402 669.14 666.3 100 78 78 21 403 669.14 666.3 96 79 76 21 404 693.25 694.3 100 82 82 21 405 635.18 636.3 100 82 82 21 406 649.2 650.3 100 80 80 21 407 750.15 751.4 93 86 80 21 408 684.15 687 100 80 80 21 409 669.14 670.3 100 100 100 21  

TABLE 90 Measured Hydrolysis Compound No. M value (M + 1)⁺ yield (%) Example No. 46 510.18 511.4 73 36 48 526.17 527.2 82 36 49 572.19 573.2 88 36 50 510.18 511.4 82 36 51 572.19 573.2 83 36  

Example 38 Human In Vitro IgE Antibody Production Suppressing Activity

The concentrations of IgE and IgG antibodies were measured by the following method according to the method described in the Journal of Immunology vol. 146, pp. 1836-1842, 1991 and the Journal of Immunology vol. 147, pp. 8-13, 1991.

Concretely, lymphocyte was separated from the peripheral venous blood of healthy person by density gradient centrifugation. The obtained lymphocyte was washed, suspended in a culture liquid (RPMI-1640 (product of Gibco Co.)+10% heat-inactivated FCS (product of Whittaker Co.)+100 μg/ml streptomycin+100 U/ml penicillin G+2 mM L-glutamine) and cultured for a week in the presence of interleukin 4 (IL-4, product of GENZYME Co.) (0.1 μg/ml), anti-CD40 antibody (antiCD40Aab, product of BIOSOURCE Co.), clone B-B20) (2 μg/ml) and interleukin 10 (IL-10, product of GENZYME Co.) (0.2 μg/ml) in the presence or absence of the compounds of the present invention described in the Tables 10 to 15 at various concentrations as test drugs.

The culture liquid was added to the culture system, the culture was continued for additional one week, and the concentrations of IgE and IgG antibodies in the supernatant were measured by sandwich ELISA method.

The measurement by ELISA method was carried out according to the known ELISA method by using rabbit anti-human IgE(ε) antibody (product of ICN Co.) as the primary antibody and biotin-anti-human IgE monoclonal antibody (G7-26, product of PharMingen Co.) as the secondary antibody for the measurement of IgE antibody concentration and anti-human IgG monoclonal antibody (G18-145, product of PharMingen Co.) as the primary antibody and biotin-donkey anti-human IgG antibody (H+L) (product of Jackson Co.) as the secondary antibody for the measurement of IgG antibody concentration, and using avidin-biotin-hourse radish peroxidase (ABC kit, product of Vector Lab.) as the enzyme and TMB (3,3′,5,5′-tetramethylbenzidine) microwell peroxidase substrate system (product of Kirkegaard & Perry Laboratories Inc.) as the substrate.

The value of IC50 and the suppressing ratio (%) at the test drug concentration of 1 μM were calculated based on the concentration attained in the absence of the compound of the present invention (reference: Ueshima, et al. American Academy of Allergy & Immunology, 1995 Annual Meeting, Program No. 818)

The results are shown in the Table 91.

TABLE 91 Antibody production suppressing action of the compound of the present invention (1 μM) IgE production IgG production Compound suppressing suppressing IC50 (μM) IC50 (μM) No. ratio (%) ratio (%) (IgE) (IgG) 93 56.2 57.9 0.738 >10 (−91.5) 415 100 −85.8 0.028 9.76 121 100 77.5 0.027 0.543 100 100 100 0.028 0.244 142 100 93.7 0.034 0.141 427 96.4 >10 0.040 >10 351 100 71.7 <0.01 0.662 370 94.7 −45.5 0.027 >1 133 100 98.2 0.042 0.228 79 100 92.4 0.040 0.489 45 99.4 −178.7 0.305 0.631 44 100 88.5 0.221 0.404  

It has been recognized from the results shown in the Table 91 that the compounds of the present invention have IgE antibody production suppressing activity.

Accordingly, these compounds are expectable as preventives and/or therapeutic agents for allergic diseases, etc., caused by the production of IgE antibody such as bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, anaphylactic shock, mite allergy, pollinosis, food allergy, urticaria, ulcerative colitis, eosinophilic gastroenteritis and drug-induced rash.

Example 39 Measurement of Cytotoxicity Using Mouse Tumor Cell L929

[Procedure] The cytotoxic action on tumor cell was measured by neutral red assay (the method described in the Journal of Tissue Culture Methodology, vol. 9, p. 7 (1984) and Toxicology Letters, vol. 24, p. 119 (1985)). Concretely, L929 cells (5×10⁴ cells/ml, 10% FCS/RPMI) were added to the wells of a 96 well ELISA plate at a rate of 100 μL each and cultured for a night, and the testing compounds of respective measurement concentrations were dissolved in DMSO solution and added to the above cells. The culture was continued for 3 days, and 2.0 μL of Neutral Red was added to attain the final concentration of 0.01%. The mixture was incubated for 1 hour at 37° C., the supernatant of the cell culture product was removed and the residue was washed twice with 200 μL of PBS to remove excess Neutral Red. Thereafter, the dye taken into the cell was extracted by adding 100 μL of 50% ethanol-1% acetic acid aqueous solution and the amount of the dye was determined by measuring the absorbance at 490 nm. The cytotoxicity was determined at each concentration of the test compound taking the cytotoxicity free from the drug as 100%. The cytotoxicity at each concentration was plotted against the concentration of each test compound and the concentration of the test compound exhibiting 50% cytotoxicity (LD50) was determined. Two sets of measurement were performed for each test under the same condition and the average value was used as the test result. The results are shown in the Table 92.

Table 92: Cytotoxic Activity of the Compounds of the Present Invention Against L929

Compound No. LD50 (μM) 4 0.375 6 2.4 37 1.02 44 1.16 45 0.22 47 0.2 59 2.4 73 >5 74 >5 79 0.98 100 0.95 121 1.8 124 0.14 133 0.33 138 0.13 142 0.54 156 0.30 167 0.18 192 0.26 248 0.085 264 0.156 268 0.16 351 0.31 370 6.8   It has been recognized from the results shown in the Table 92 that the compounds of the present invention have cytotoxic action on L929.

Example 40 Carcinostatic Action on Cultured Human Cancer Cell

[Prodedure] Cultured human cancer cells (39 kinds) were scattered on a 96 well plate, a solution of the testing substance (5-stage concentrations starting from 10⁻⁴ M and diluted 10 times to 10.8 M) was added thereto on the next day and the cells were cultured for 2 days. The number of the proliferated cells on each plate was determined by colorimetric quantitative analysis with sulforhodamine B. The concentration to suppress the proliferation of cell by 50% (GI50) compared with a control (free from the testing substance) was calculated and the following values (concentrations) were calculated based on the number of cells immediately before the addition of the testing substance.

TGI: concentration to suppress the proliferation to a standard cell number (free from the change of apparent number of cells)

LC50: concentration to decrease the number of cells to 50% of the standard cell number (cytocidal activity)

The proliferation-suppressing results of three testing substances 124, 257 and 983 on 9 representative cancer cell strains are collectively shown in the Tables 93 to 95.

TABLE 93 Compound Cancer cell No. strain GI50 (μM) TGI (μM) LC50 (μM) 983 HBC-4 0.59 76 >100 SF-539 0.6 20 51 HCT-15 0.1 30 >100 NCI-H460 0.33 16 95 LOX-IMVI 0.26 3.4 50 OVCAR-8 4.2 40 >100 RXF-631L 0.4 18 96 MKN-74 0.46 25 >100 PC-3 4.5 31 >100  

TABLE 94 Compound Cancer cell No. strain GI50 (μM) TGI (μM) LC50 (μM) 124 HBC-4 0.25 18 57 SF-539 0.13 26 57 HCT-15 0.17 17 58 NCI-H460 0.091 14 69 LOX-IMVI 0.09 10 45 OVCAR-8 3.1 23 57 RXF-631L 0.13 12 38 MKN-74 0.086 16 >100 PC-3 10 24 55  

TABLE 95 Compound Cancer cell No. strain GI50 (μM) TGI (μM) LC50 (μM) 257 HBC-4 <0.01 18 58 SF-539 <0.01 17 51 HCT-15 <0.01 17 53 NCI-H460 <0.01 11 44 LOX-IMVI <0.01 10 44 OVCAR-8 <0.01 23 59 RXF-631L <0.01 14 42 MKN-74 <0.01 16 >100 PC-3 10 26 69  

It has been recognized from the results shown in the Tables 93 to 95 that the compounds of the present invention have proliferation suppressing action on main cultured human cancer cells.

The results of the Examples 39 and 40 show that the compounds of the present invention are useful also as carcinostatic agents.

Possibility of Industrial Utilization

The anthranilic acid derivatives of the present invention or their medically permissible salts or solvates exhibit strong cytotoxic activity and IgE antibody production suppressing action. Accordingly, the anthranilic acid derivatives of the present invention are clinically applicable as a therapeutic agent for cancer or a preventive or therapeutic agent for allergic diseases. 

1. The anthranilic acid derivative expressed by the following formula (2) or its phannacologically permissible salt or solvate:

  wherein, Y² is the group of the formula (3)-1, (3)-2, (5)-1, or (5)-2:

  {in the formulas (3)-1 and (3)-2, Z is a straight-chain, branched or cyclic saturated, unsaturated or aromatic C1 to C12 hydrocarbon group substituted by one or more —NR¹⁰R¹¹, —COOR¹², —(C═O)NR¹³R¹⁴, —(C═O)R¹⁵ or —OR¹⁶ (the C1 to C12 hydrocarbon group is optionally substituted by a substituent L (L is a C1 to C6 alkyl group, a halogen atom, —NO₂ or —CN)), a 3 to 8-membered saturated ring containing one or plural —NR¹⁷—, —O— or —S— in the ring and optionally containing one or more —C(═O)— groups in the ring, a C1 to C4 straight or branched-chain saturated or unsaturated hydrocarbon group having one or two double bonds or triple bonds and optionally substituted by the above 3 to 8-membered ring, or a C5 to C10 straight or branched-chain saturated or unsaturated hydrocarbon group substituted by a monocyclic or bicyclic aromatic ring containing one or more hetero-atoms selected from the group consisting of an oxygen, nitrogen and sulfur atom in the ring (the aromatic ring is optionally substituted by the substituent L), the groups R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are each independently hydrogen atom, a straight or branched-chain C1 to C6 alkyl group which is optionally substituted, a C7 to C11 aralkyl group which is optionally substituted, a C6 to C10 aryl group which is optionally substituted (the substituent is a halogen atom, —OH, a C1 to C4 alkoxy group, —CN, —NO₂ or —COOR¹⁸), or a group selected from the following formulas (4)-1, (4)-2 and (4)-3; the groups R¹⁰ and R¹¹, or R¹³ and R¹⁴ may together form a 3 to 12-membered ring optionally containing one or more —O—, —S—, —NR¹⁸— or —(C═O)— groups;

  (in the formulas (4)-1, (4)-2 and (4)-3, Q is a C1 to C10 alkyl group which is optionally substituted, a C2 to C6 alkenyl group which is optionally substituted, a C1 to C6 alkoxy group which is optionally substituted, a C7 to C11 aralkyl group which is optionally substituted, a C7 to C11 aralkyloxy group which is optionally substituted (the substituent is a halogen atom, —OH, —CN, —NO₂, —COOR¹⁹ or phenoxy group), dimethylamino group, morpholino group or a monocyclic or bicyclic aromatic hydrocarbon group which may have one or more hetero-atoms selected from oxygen, nitrogen and sulfur atoms, (when a monocyclic or bicyclic aromatic hydrocarbon group which may have one or more hetero-atoms is selected in the above case, the ring is optionally substituted at arbitrary positions independently by one or plural substituents selected from the group consisting of halogen atom, —OH, —NO₂, —CN, —COOR¹⁹, —NR¹⁹R²⁰, straight or branched-chain C1 to C6 alkyl group, straight or branched-chain C1 to C6 alkoxy group (in this case, the substituents at adjacent positions may form an acetyl bond), straight or branched-chain C1 to C6 alkylthio group, straight or branched-chain C1 to C6 alkylsulfonyl group, straight or branched-chain C1 to C6 acyl group, straight or branched-chain C1 to C6 acylamino group, trihalomethyl group, trihalomethoxy group, phenyl group, and phenoxy group which is optionally substituted by one or more halogen atoms), the groups R¹⁹ and R²C are each independently hydrogen atom or a C1 to C4 alkyl group), the group R¹⁸ is hydrogen atom or a C1 to C4 alkyl group, the group X³ is —(C═O)—, —O—, —S—, —(S═O)—, —(O═S═O)—, —NR²¹—, *—NR²¹(C═O) or *—(C═O)NR²¹ (the sign (*—) representing a bond means the bonding to the benzene ring or the naphthalene ring in the formula (3)-1 or the formula (3)-2), the group R²¹ is hydrogen atom or a C1 to C4 hydrocarbon group which is optionally substituted by halogen, the groups R⁵ and R⁶ are each independently hydrogen atom, a halogen atom, —NO₂, —CO₂H, —CN, —OR²², —NH(C═O)R²², —(C═O)NHR²² or a C1 to C4 straight or branched-chain saturated or unsaturated hydrocarbon group which is optionally substituted by halogen atom, the group R²² is a C1 to C3 hydrocarbon group which is optionally substituted by hydrogen atom or halogen atom},

  {in the formulas (5)-1 and (5)-2, the group R⁷ is hydrogen atom or a substituted or unsubstituted straight-chain, branched or alicyclic saturated or unsaturated C1 to C12 hydrocarbon group having one or two double bonds or triple bonds [in this case, the substituent is a halogen atom, —NO₂, —CN, a substituted or unsubstituted phenyl group (in this case, the substituent is a halogen atom, —NO₂, —ON, —CF3 or a C1 to C4 hydrocarbon group), or a substituted or unsubstituted 5 to 8-membered cycloalkyl group (in this case, the substituent is a halogen atom or a C1 to C4 hydrocarbon group)], the group X4 is —(C═O)—, —O—, —S—, —(S═O)—, —(O═S═O)—, —NR²³—, *—NR²³CO or *—CONR²³ (the group R²³ is hydrogen atom or a C1 to C4 hydrocarbon group which is optionally substituted by halogen atom (in this case, the sign (*—) means the bonding to the benzene ring or the naphthalene ring of the formula (5)-1 or the formula (5)-2), the group R⁷ is not hydrogen atom when the group X⁴ is —(C═O)—, —(S═O)—, —(O═S═O)— or *—NR²³(C═O)—, the groups R⁸ and R⁹ are each independently hydrogen atom, a halogen atom, —NO₂, —CO₂H, —CN, —OR²⁴, —NH(C═O)R²⁴, —(C—O)NHR²⁴ or a straight or branched-chain saturated or unsaturated C1 to C4 hydrocarbon group which is optionally substituted by halogen atom (the group R²⁴ is hydrogen atom or a C1 to C3 hydrocarbon group which is optionally substituted by halogen atom)}, the group X¹ is —(C═O)—, —O—, —S—, —(S═O)—, —(O═S═O)— or —CH₂, the group X² is O or S, the groups R¹ and R² are each independently hydrogen atom, a halogen atom, —NO₂, —CO₂H, —CN, —OR²⁵, —NH(C═O)R²⁵, —(C═O)NHR²⁵ or a C1 to C4 straight or branched-chain saturated or unsaturated hydrocarbon group which is optionally substituted by halogen atom, the group R²⁵ is hydrogen atom or a C1 to C3 hydrocarbon group which is optionally substituted by halogen atom, the groups R³ and R⁴ are each independently hydrogen atom or a C1 to C4 hydrocarbon group, the group A is N, N→O or N⁺—CH₃, and n is an integer of 0 to
 3. 2. The anthranilic acid derivative claimed in claim 1, wherein Y² is the group of the formula (3)-1 or the formula (3)-2, or its pharmacologically permissible salt or solvate.
 3. The anthranilic acid derivative claimed in claim 1, wherein the group Y² is expressed by the formula (5)-1 or the formula (5)-2, or its pharmacologically permissible salt or solvate.
 4. The anthranilic acid derivative described in claim 1, wherein the group Y² in the formula (2) is expressed by the formula (5)-1, the formula (5)-2, a formula (9)-1, a formula (9)-2 or a formula (9)-3, or its pharmacologically permissible salt or solvate:

 
 5. The anthranilic acid derivative claimed in any one of claims 1, 2, or 4 wherein the Group Z is a straight-chain, branched or cyclic saturated, unsaturated or aromatic C1 to C12 hydrocarbon group substituted by one or more —NR¹⁰R¹¹, —COOR¹², —(C═O)NR¹³R¹⁴, —(C═O)R¹⁵ or —OR¹⁶ [the C1 to C12 hydrocarbon group is optionally further substituted by substituent L (L is a C1 to C6 alkyl group, halogen atom, —NO₂ or —CN)], or its pharmacologically permissible salt or solvate.
 6. The anthranilic acid derivative claimed in any one of claims 1, 2, or 4 wherein the group Z is a saturated 3 to 8-membered ring containing one or plural —NR¹⁷—, —O— or —S— groups and optionally containing one or more —C(═O)— groups in the ring, or a C1 to C4 straight or branched-chain saturated or unsaturated hydrocarbon group having one or two double bonds or triple bonds and optionally substituted by the above 3 to 8-membered ring, or its pharmacologically permissible salt or solvate.
 7. The anthranilic acid derivative claimed in any one of claims 1, 2, or 4 wherein the group Z is a C5 to C10 straight or branched-chain saturated or unsaturated hydrocarbon group substituted by a monocyclic or bicyclic aromatic ring containing one or more hetero-atoms selected from oxygen, nitrogen and sulfur atom in the ring (the aromatic ring is optionally substituted by a substituent L), or its pharmacologically permissible salt or solvate.
 8. A pharmaceutical composition comprising an effective amount of an anthranilic acid derivative claimed in any one of the claims 1, 2, 3, or 4, or its pharmacologically permissible salt or solvate, and a pharmacologically permissible carrier.
 9. The pharmaceutical composition claimed in claim 8, wherein the effective amount of the anthranilic acid derivative is an amount having cytotoxic activity.
 10. A method for treatment of cancer comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition claimed in claim 8 and wherein the effective amount of the anthranilic acid derivative is an amount to treat cancer.
 11. The pharmaceutical composition claimed in claim 8, wherein the effective amount of an anthranilic acid derivative is an amount having IgE antibody production suppressing action.
 12. A method for treatment of allergic diseases comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition claimed in claim 8 and wherein the effective amount of the anthranilic acid derivative is an amount to treat allergic diseases.
 13. The method claimed in claim 12, wherein said allergic disease is at least one member selected from the group consisting of bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, anaphylactic shock, mite allergy, pollinosis, food allergy, urticaria, ulcerative colitis, eosinophilic gastroenteritis and drug-induced rash. 